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Handbook of Drug-Nutrient Interactions

VIEWS: 4,171 PAGES: 583

									Handbook of
           Edited by

  Joseph I. Boullata, PharmD
 Vincent T. Armenti, MD, PhD
      NUTRITION              AND        HEALTH
               Adrianne Bendich, Series Editor

Handbook of Drug–Nutrient Interactions, edited by Joseph I. Boullata and
    Vincent T. Armenti, 2004
Nutrition and Oral Medicine, edited by Riva Touger-Decker, David A. Sirois,
    and Connie C. Mobley, 2004
IGF, Nutrition, and Health, edited by M. Sue Houston, Jeffrey M. P. Holly, and Eva
     L. Feldman, 2004
Epilepsy and the Ketogenic Diet, edited by Carl E. Stafstrom and Jong M. Rho,
Nutrition and Bone Health, edited by Michael F. Holick and Bess Dawson-
     Hughes, 2004
Diet and Human Immune Function, edited by David A. Hughes, L. Gail
     Darlington, and Adrianne Bendich, 2004
Beverages in Nutrition and Health, edited by Ted Wilson and Norman J.
     Temple, 2004
Handbook of Clinical Nutrition and Aging, edited by Connie Watkins Bales
     and Christine Seel Ritchie, 2004
Fatty Acids: Physiological and Behavioral Functions, edited by David I.
     Mostofsky, Shlomo Yehuda, and Norman Salem, Jr., 2001
Nutrition and Health in Developing Countries, edited by Richard D. Semba
     and Martin W. Bloem, 2001
Preventive Nutrition: The Comprehensive Guide for Health Professionals,
     Second Edition, edited by Adrianne Bendich and Richard J.
     Deckelbaum, 2001
Nutritional Health: Strategies for Disease Prevention, edited by Ted
     Wilson and Norman J. Temple, 2001
Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide
     for Health Professionals, edited by John D. Bogden and Leslie M. Klevey,
Primary and Secondary Preventive Nutrition, edited by Adrianne Bendich
     and Richard J. Deckelbaum, 2000
The Management of Eating Disorders and Obesity, edited by David J.
     Goldstein, 1999
Vitamin D: Physiology, Molecular Biology, and Clinical Applications,
     edited by Michael F. Holick, 1999
Preventive Nutrition: The Comprehensive Guide for Health Professionals,
     edited by Adrianne Bendich and Richard J. Deckelbaum, 1997

Edited by
Temple University School of Pharmacy, Philadelphia, PA
Temple University School of Medicine, Philadelphia, PA

Foreword by

Albany College of Pharmacy, Albany, NY

            HUMANA PRESS
            TOTOWA, NEW JERSEY
© 2004 Humana Press Inc.
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All papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the

Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published
and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and
dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as
new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions
constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change
in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a
new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for
individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status
of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions
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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

E-ISBN 1-59259-781-5
Library of Congress Cataloging-in-Publication Data
Handbook of drug-nutrient interactions / edited by Joseph I.
   Boullata, and Vincent T. Armenti ; foreword by Margaret
     p. ; cm. -- (Nutrition and health)
   Includes bibliographical references and index.
   ISBN 1-58829-249-5 (alk. paper)
   1. Drug-nutrient interactions--Handbooks, manuals, etc.
 I. Boullata, Joseph I. II. Armenti, Vincent T. III. Series:
 Nutrition and health (Totowa, N.J.)
   [DNLM: 1. Food-Drug Interactions--Handbooks. 2. Nutrition
 --Handbooks. QV 39 H23636 2004]
 RM302.4.H355 2004
 615'.70452--dc22                                                                                       2003021008
Series Editor’s Introduction

   The Nutrition and Health series of books have an overriding mission to provide health
professionals with texts that are considered essential because each includes (1) a synthe-
sis of the state of the science; (2) timely, in-depth reviews by the leading researchers in
their respective fields; (3) extensive, up-to-date, fully annotated reference lists; (4) a
detailed index; (5) relevant tables and figures; (6) identification of paradigm shifts and
the consequences; (7) virtually no overlap of information between chapters, but targeted,
interchapter referrals; (8) suggestions of areas for future research; and (9) balanced, data-
driven answers to patient/health professionals’ questions that are based on the totality of
evidence rather than the findings of any single study.
   The series volumes are not the outcome of a symposium. Rather, each editor has the
potential to examine a chosen area with a broad perspective, both in subject matter as well
as in the choice of chapter authors. The international perspective, especially with regard
to public health initiatives, is emphasized where appropriate. The editors, whose trainings
are both research- and practice-oriented, have the opportunity to develop a primary
objective for their book, define the scope and focus, and then invite the leading authorities
from around the world to be part of their initiative. The authors are encouraged to provide
an overview of the field, discuss their own research, and relate the research findings to
potential human health consequences. Because each book is developed de novo, the
chapters are coordinated so that the resulting volume imparts greater knowledge than the
sum of the information contained in the individual chapters.
   The Handbook of Drug–Nutrient Interactions, edited by Joseph I. Boullata and Vincent
T. Armenti, is a critical addition to the Nutrition and Health Series and fully exemplifies
the goals of the series. Both editors are internationally recognized leaders in the field
of nutrition and drug therapy. Both are excellent communicators and have worked
tirelessly to develop a book that is destined to be the benchmark in the field because of
its extensive, in-depth chapters covering the most important aspects of the complex
interactions between diet and its nutrient components, health status, developmental stage,
growth, and aging and the effects of drugs. The editors have chosen 41 of the most well-
recognized and respected authors from around the world to contribute the 26 informative
chapters in the volume. Key features of this comprehensive volume include more than
thirty extensive tables and figures that provide the reader with excellent sources of
detailed information about drug–nutrient interactions.
   The editors clearly understand the seriousness of the issue of drug–nutrient interac-
tions. They have stated that “In the care of patients, both drug therapy and nutritional
therapy are critical. The potential for drugs and nutrients to interact with each other is
significant, but unrecognized by many clinicians. These interactions may result in thera-
peutic failure or adverse effects of the drug, or alterations in the nutritional status of the
patient—in either case impacting the patient’s outcome.”

vi                                                                Series Editor’s Introduction

   The book chapters are logically organized to provide the reader with all of the basics
of both drug metabolism and nutrition in the first section, Overview of Drug–Nutrient
Interactions. Unique chapters in this section include an introductory chapter that de-
scribes the basics of drug metabolism followed by a more in-depth chapter that includes
a thorough discussion of the drug-metabolizing enzymes in the critical chapter that
includes 325 references. There is also a comprehensive review of the basics of the me-
tabolism of the major dietary nutrients.
    Part II contains two chapters that examine the effects of either under- or overnutrition
(obesity) on drug disposition and their effects. Specialized topics in the third section
include the effects of concomitant consumption of foods and a drug and include a detailed
description of Food and Drug Administration requirements for conducting a clinical
study on a fasted or fed state. Non-nutritive components of the diet such as herbs, caffeine,
charcoal broiling of foods, and alcohol also affect drug efficacy and these effects are
presented in extensive tables that organize the data clearly for the reader. The effects of
grapefruit juice, garlic, ginkgo and other key herbs as well as nutrient–nutrient interac-
tions are reviewed in separate, comprehensive chapters.
   Cutting-edge discussions of the roles of the major drugs used by patients are covered
in individual chapters and related to the dietary factors that can either interfere with or
enhance efficacy. Drugs affecting the cardiovascular system and the nervous system,
with emphasis on antiepileptics, are reviewed in depth. Specific emphasis is given to the
effects of dietary minerals on drug pharmacokinetics and pharmacodynamics depending
on whether the individual is deficient in the specific mineral. Likewise, supplementation
with various dietary factors including folate, vitamin D, vitamin K, and calcium is also
   Of particular relevance to clinicians are the chapters in Part V that examine drug
nutrient interactions by life stages. Chapters include infancy and childhood, pregnancy
and lactation, and the elderly, stages that have special considerations when examining
the types of drugs used by the different groups and the varied nutritional requirements of
these life stages.
   The final section looks at drug–nutrient interactions in individuals who have either
chronic diseases or special needs for certain classes of drugs. The chapter on cancer
patients is particularly sensitive to the potential for drugs to affect the precarious health
balance in these patients. Transplant patients also have unique needs and this chapter
contains a valuable table that provides details about the nutrient requirements of trans-
plant patients posttransplant. Several chapters examine the effects of chronic infections
including HIV, tuberculosis, and hepatitis. Another concentrates on the effects of autoim-
mune diseases including rheumatoid arthritis, diabetes, and lupus, the drugs used in
treatment, and the interactions of the disease, drug, and nutritional status. The final
chapter looks at the role of enteral nutrition in affecting drug delivery, disposition, and
clearance, another important clinically focused chapter.
    Of great importance, the editors and authors have provided chapters that balance the
most technical information with discussions of its importance for clients and patients as
well as graduate and medical students, health professionals, and academicians. Hall-
marks of the chapters include complete definitions of terms with the abbreviation fully
defined for the reader and consistent use of terms between chapters. There are numerous
vii                                                               Series Editor’s Introduction

relevant tables, graphs, and figures as well as up-to-date references; all chapters include
a conclusion section that provides the highlights of major findings. The volume contains
a highly annotated index and within chapters, readers are referred to relevant information
in other chapters.
   This important text provides practical, data-driven resources based on the totality of
the evidence to help the reader evaluate the critical role of nutrition, especially in at-risk
populations, in optimizing drug efficacy. The overarching goal of the editors is to provide
fully referenced information to health professionals so they may have a balanced perspec-
tive on the value of foods and nutrients that are routinely consumed and how these can
help to assure that drugs can deliver their maximum benefits with minimal adverse
effects. Finally, it must be noted that all of the authors and the editors agree that much
more research is required to be able to give the best advice to patients with regard to drug–
nutrient interactions.
   In conclusion, Handbook of Drug–Nutrient Interactions provides health professionals in
many areas of research and practice with the most up-to-date, well-referenced, and easy-to-
understand volume on the importance of nutrition in optimizing drug efficacy and avoiding
adverse effects. This volume will serve the reader as the most authoritative resource in the
field to date and is a very welcome addition to the Nutrition and Health Series.
                                                             Adrianne Bendich, PhD, FACN
                                                                           Series Editor

   Although there is a great deal of literature regarding drug–nutrient interactions (DNIs),
there are limited sources of up-to-date comprehensive information. The Handbook of
Drug–Nutrient Interactions admirably fills this gap. The editors, Dr. Joseph I. Boullata
and Dr. Vincent T. Armenti, have a wealth of experience in this therapeutic area and have
assembled a fine cadre of chapter authors who have individually contributed their high
level of expertise.
   As treatment for many diseases becomes increasingly complex with multiple drug
therapies scheduled at varying times, the need to identify clinically significant DNIs is
an essential part of medication management. This is a shared responsibility between
health care professionals to interpret available data and individualize an approach to
therapy that is compatible with the patient’s disease state, life stage, and dietary intake.
   Awareness of the significance of drug–food interactions is generally lacking. Although
many texts contain lengthy lists of possible interactions, few data are provided for the
clinician to gain an understanding of the mechanism of action of the interaction and
subsequently apply the information to a particular patient or group of patients. For example,
in the management of patients with HIV-AIDS who are taking complex prescribed drug
regimens, herbal products, and nutritional supplements, many of which are affected by
dietary intake, careful attention to DNIs is a critical component of therapy. Clinicians
need to take account of not only the well-documented interactions between drugs and
nutrients, but also the less obvious effects on drug–nutrient disposition and metabolism.
The current text provides the reader with this valuable insight.
   Designing a regimen that is both safe and effective for the patient is an important part
of collaborative drug therapy management. As such, this comprehensive handbook will
serve as a resource for pharmacists, dietitians, nurses, and physicians as they partner to
enable better drug therapy adherence and therapeutic outcomes for their patients. In
addition, the Handbook of Drug–Nutrient Interactions will serve as an excellent resource
for both educators and students in raising the level of awareness and knowledge of the
mechanisms of DNIs such that their consideration is given a level of importance similar
to that of drug–drug interactions, which are more consistently reviewed.
                                                              Margaret Malone, PhD, FCCP
                                                        Department of Pharmacy Practice
                                                  Albany College of Pharmacy, Albany, NY


   Although the influence of nutrition on health is obvious, its critical role in the care of
patients is not as widely recognized. In caring for patients, more attention is often paid
to the role of drug therapy. The field of clinical nutrition actually overlaps with the field
of pharmacotherapy at several points, but none more clearly than at the interaction of drug
and nutrient. A drug–nutrient interaction is considered the result of a physical, chemical,
physiologic, or pathophysiologic relationship between a drug and nutrient(s)/food that is
deemed significant when the therapeutic response is altered or the nutritional status
compromised. We felt that a current reference book on this subject was long overdue, so
we have put together this Handbook of Drug–Nutrient Interactions.
   The handbook is intended for use by physicians, pharmacists, nurses, dietitians, nutri-
tionists, and others, in training or in clinical practice, to better manage drug–nutrient
interactions in their patients. This topic is particularly timely with so much attention
being paid to the issue of patient safety in the current health care delivery system.
Although a number of manuals exist that provide extensive lists of documented and
potential drug–nutrient interactions, this handbook takes a scientific look behind many
of those interactions, examines their relevance, gives recommendations, and suggests
specific areas requiring research. This handbook provides clinicians with a guide for use
in understanding, identifying, or predicting, and ultimately preventing or managing sig-
nificant adverse drug–nutrient interactions to optimize patient care. We hope this hand-
book challenges clinicians to become more aware of potential drug–nutrient interactions,
document them regularly, and carry out research projects to clarify their mechanisms and
clinical significance. Much more needs to be known about drug–nutrient interactions
than is currently appreciated. Some topics have yet to amass enough information to allow
inclusion in a chapter; others are as yet unanticipated. For example, how long will it be
before genetic engineering allows relatively inexpensive production of certain pharma-
ceuticals by plants? Without placing a value judgment on that notion, it becomes clear
that the issue of drug–nutrient interactions has moved past the problems of how to time
drug administration around meals.
   The book begins with a perspective on the topic (Chapter 1), and is followed by
overviews of drug disposition, nutrient disposition, and enzyme systems involved in both
drug and nutrient metabolism (Chapters 2–4). These chapters allow the reader, regardless
of discipline, to gain a sense of the topic and the underlying foundation that is needed in
the remainder of the book. Two chapters discuss the effect of nutritional status on drug
disposition and effect (Chapters 5–6), a topic often overlooked. The next group of chap-
ters discusses the influence of food, nutrients, and non-nutrient dietary components on
drug disposition and effect (Chapters 7–12). Given the widespread use of dietary supple-
ments, interactions with drugs and with nutrients by this diverse group of substances—
some of which behave more like drugs than nutrients—these chapters are most relevant.
The influence of medications on nutrient status is presented both generally and in regard
xii                                                                                   Preface

to specific groups of drugs or nutrients (Chapters 13–17). Another set of chapters dis-
cusses drug–nutrient interactions that are relevant to various stages of the life cycle or to
specific patient groups or conditions (Chapters 18–26).
    There is no one best way to approach drug–nutrient interactions, and we have included
some topics not typically considered in such a presentation. Clearly, not every docu-
mented drug–nutrient interaction identified in vitro, ex vivo, in animal models, or in
human studies is covered. Not discussed are the sequential interactions between nutri-
ents, disease and drugs (e.g., micronutrients impacting HIV disease, which then influ-
ences drug disposition). One multifaceted topic deserving of discussion, but not included,
is the set of interactions involving parenteral nutrition, in terms of both the effect on drug
disposition and the impact of each nutrient or combination of nutrients on each other and
on concurrently infused drugs. However, parenteral drug–nutrient interactions could fill
an entire book. Overlap is almost unavoidable in a book on drug–nutrient interactions,
but we have tried to avoid major sections of redundancy. For example, although the chapter
on interactions involving folate mentions the antiepileptics, a chapter entirely devoted to
antiepileptic interactions follows. Similarly, the interactions involving grapefruit juice are
touched on in several chapters, but a more in-depth discussion is reserved for the chapter
dedicated to that topic. The more detailed chapter on the elderly is in part related to
the historic relevance of drug–nutrient interactions in this group.
    What we have attempted to provide is a bit more than a listing of common interactions.
The authors, some having spent many years with their subject matter, provide a frame-
work for understanding many of the more common, and some less common, drug–
nutrient interactions, including the mechanisms and clinical approaches to their
management. We hope that this Handbook of Drug–Nutrient Interactions helps make the
case that the issue of drug–nutrient interactions is a significant one for clinicians and
researchers alike. We are grateful to the authors for their work, and excited about this
compilation, although we are looking forward to new information on drug–nutrient in-
teractions as it continues to emerge. We would welcome comments from readers that will
help improve the breadth, depth, and quality of this book and the care of patients.
                                                               Joseph I. Boullata, PharmD
                                                              Vincent T. Armenti, MD, PhD

Series Editor’s Introduction ........................................................................................... v
Foreword ....................................................................................................................... ix
Preface ........................................................................................................................... xi
Contributors .................................................................................................................. xv
Value-Added eBook/PDA ........................................................................................ xvii
                       1    A Perspective on Drug–Nutrient Interactions.................................. 3
                            Joseph I. Boullata and Jacqueline R. Barber
                       2    Drug Disposition and Response ..................................................... 27
                            Robert B. Raffa
                       3    Drug-Metabolizing Enzymes and P-Glycoprotein ........................ 43
                            Thomas K. H. Chang
                       4    Nutrient Disposition and Response ................................................ 69
                            Francis E. Rosato, Jr.
                      AND EFFECT
                       5    The Impact of Protein-Calorie Malnutrition on Drugs .................. 83
                            Charlene W. Compher
                       6    Influence of Obesity on Drug Disposition and Effect ................. 101
                            Joseph I. Boullata
                       AND EFFECT
                       7    Drug Absorption With Food ........................................................ 129
                            David Fleisher, Burgunda V. Sweet, and Ameeta Parekh
                       8    Effects of Specific Foods and Non-Nutritive Dietary
                              Components on Drug Metabolism ........................................... 155
                            Karl E. Anderson
                       9    Grapefruit Juice–Drug Interaction Issues .................................... 175
                            David G. Bailey
                    10      Nutrients That May Optimize Drug Effects ................................ 195
                            Imad F. Btaiche and Michael D. Kraft
                    11      Dietary Supplement Interactions With Medication ..................... 217
                            Jeffrey J. Mucksavage and Lingtak-Neander Chan

xiv                                                                                                                     Contents

                    12      Dietary Supplement Interaction With Nutrients .......................... 235
                            Mariana Markell
                    13      Drug-Induced Changes to Nutritional Status ............................... 243
                            Jane M. Gervasio
                    14      Cardiac Drugs and Nutritional Status .......................................... 257
                            Honesto M. Poblete, Jr. and Raymond C. Talucci, II
                    15      Drug–Nutrient Interactions Involving Folate .............................. 271
                            Leslie Schechter and Patricia Worthington
                    16      Effects of Antiepileptics on Nutritional Status ............................ 285
                            Mary J. Berg
                    17      Drug–Nutrient Interactions That Impact Mineral Status ............. 301
                            Sue A. Shapses, Yvette R. Schlussel, and Mariana Cifuentes
                    18      Drug–Nutrient Interactions in Infancy and Childhood ................ 331
                            Deborah A. Maka, Lori Enriquez, and Maria R. Mascarenhas
                    19      Drug–Nutrient Interaction Considerations in Pregnancy
                              and Lactation ............................................................................ 345
                            Kathleen L. Hoover, Marcia Silkroski, Leslie Schechter,
                              and Patricia Worthington
                    20      Drug–Nutrient Interactions in the Elderly ................................... 363
                            Tanya C. Knight-Klimas and Joseph I. Boullata
                    21   Drug–Nutrient Interactions in Patients With Cancer................... 413
                         Todd W. Canada
                 22 Drug–Nutrient Interactions in Transplantation ............................ 425
                         Matthew J. Weiss, Vincent T. Armenti, and Jeanette M. Hasse
                 23 Drug–Nutrient Interactions and Immune Function ..................... 441
                         Adrianne Bendich and Ronit Zilberboim
                 24 Drug–Nutrient Interactions in Patients
                             With Chronic Infections ........................................................... 479
                         Steven P. Gelone and Judith A. O’Donnell
                 25 Antimicrobial–Nutrient Interactions: An Overview ..................... 499
                         Allison Wood Wallace
                 26 Drug–Nutrient Interactions in Patients Receiving
                             Enteral Nutrition ....................................................................... 515
                         Carol J. Rollins
Index ........................................................................................................................... 553

KARL E. ANDERSON, MD • Departments of Preventive Medicine and Community Health,
   Internal Medicine, and Pharmacology and Toxicology, University of Texas
   Medical Branch, Galveston, TX
VINCENT T. ARMENTI, MD, PhD • Department of Surgery, Temple University School
   of Medicine, Philadelphia, PA
DAVID G. BAILEY, BSC Pharm, PhD • Department of Medicine and Lawson Health
   Research Institute, London Health Sciences Centre and Department of Physiology
   and Pharmacology, University of Western Ontario, London, Ontario, Canada
JACQUELINE R. BARBER, PharmD, BCNSP • Department of Pharmacy, Methodist Hospital
   Health Services, St. Louis Park, MN
ADRIANNE BENDICH, PhD • Medical Affairs, GlaxoSmithKline Consumer Healthcare,
   Parsippany, NJ
MARY J. BERG, PharmD • College of Pharmacy, University of Iowa, Iowa City, IA
JOSEPH I. BOULLATA, PharmD, BCNSP • Department of Pharmacy Practice,
   Temple University School of Pharmacy, Philadelphia, PA
IMAD F. BTAICHE, PharmD, BCNSP • College of Pharmacy, University of Michigan and
   Department of Pharmacy Services, University of Michigan Hospitals and Health
   Centers, Ann Arbor, MI
TODD W. CANADA, PharmD, BCNSP • Division of Pharmacy, The University of Texas
   M.D. Anderson Medical Center, Houston, TX
LINGTAK-NEANDER CHAN, PharmD, BCNSP • Colleges of Pharmacy and Medicine,
   University of Illinois at Chicago, Chicago, IL
THOMAS K. H. CHANG, PhD • Faculty of Pharmaceutical Sciences, University
   of British Columbia, Vancouver, British Columbia, Canada
MARIANA CIFUENTES, PhD • Instituto de Nutrición y Techcologia de los Alimentos,
   University of Chile, Santiago, Chile
CHARLENE W. COMPHER, PhD, RD, FADA, CNSD • School of Nursing, University
   of Pennsylvania, Philadelphia, PA
LORI ENRIQUEZ, RD, CSP, CNSD • Department of Clinical Nutrition, The Children’s
   Hospital of Philadelphia, Philadelphia, PA
DAVID FLEISHER, PhD • Department of Pharmaceutical Sciences, College of Pharmacy,
   University of Michigan, Ann Arbor, MI
STEVEN P. GELONE, PharmD • Department of Pharmacy Practice, Temple University
   School of Pharmacy, Philadelphia, PA
JANE M. GERVASIO, PharmD, BCNSP • Methodist Hospital at Clarian Health Partners,
   Indianapolis, IN
JEANETTE M. HASSE, PhD, RD, FADA, CNSD • Baylor Institute of Transplantation Sciences,
   Baylor University Medical Center, Dallas, TX

xvi                                                                    Contributors

KATHLEEN L. HOOVER, MEd, IBCLC • Department of Public Health, Maternal, Child and
   Family Health, Philadelphia, PA
TANYA C. KNIGHT-KLIMAS, PharmD, CGP, FASCP • Department of Pharmacy Practice,
   Temple University School of Pharmacy, Philadelphia, PA
MICHAEL D. KRAFT, PharmD • College of Pharmacy, University of Michigan
   and Department of Pharmacy Services, University of Michigan Hospitals
   and Health Centers, Ann Arbor, MI
DEBORAH A. MAKA, PharmD • Department of Pharmacy Services, The Children’s
   Hospital of Philadelphia, Philadelphia, PA
MARIANA MARKELL, MD • Division of Renal Disease, State University of New York
   Health Science Center, Brooklyn, NY
MARIA R. MASCARENHAS, MD • Division of Gastroenterology and Nutrition, The
   Children’s Hospital of Philadelphia, Philadelphia, PA
JEFFREY J. MUCKSAVAGE, PharmD, BCPS • College of Pharmacy, University of Illinois
   at Chicago, Chicago, IL
JUDITH A. O’DONNELL, MD • Department of Medicine, Drexel University College
   of Medicine and School of Public Health, MCP Hospital-Division of Infectious
   Diseases, Philadelphia, PA
AMEETA PAREKH, PhD • Office of Clinical Pharmacology and Biopharmaceutics,
   Center for Drug Evaluation and Research, U.S. Food and Drug Administration,
   Rockville, MD
HONESTO M. POBLETE, JR., MD • Department of Surgery, Drexel University College
   of Medicine, Philadelphia, PA
ROBERT B. RAFFA, PhD • Department of Pharmaceutical Sciences, Temple University
   School of Pharmacy, Philadelphia, PA
CAROL J. ROLLINS, MS, RD, CNSD, PharmD, BCNSP • University of Arizona College
   of Pharmacy and Nutrition Support Team, University Medical Center, Tucson, AZ
FRANCIS E. ROSATO, JR., MD • Department of Surgery, Thomas Jefferson University
   Hospital, Philadelphia, PA
LESLIE SCHECHTER, PharmD • Department of Pharmacy, Thomas Jefferson University
   Hospital, Philadelphia, PA
YVETTE R. SCHLUSSEL, PhD • Department of Nutritional Sciences, Rutgers, The State
   University, New Brunswick, NJ
SUE A. SHAPSES, PhD, RD • Department of Nutritional Sciences, Rutgers, The State
   University, New Brunswick, NJ
MARCIA SILKROSKI, RD • Nutrition Advantage, Chester Springs, PA
BURGUNDA V. SWEET, PharmD • Drug Information and Investigational Services, College
   of Pharmacy, University of Michigan Health System, Ann Arbor, MI
RAYMOND C. TALUCCI, II, MD, FACS • Department of Surgery, Drexel University
   College of Medicine, Hahnemann Hospital, Philadelphia, PA
ALLISON WOOD WALLACE, PharmD, BCPS • Duke University Medical Center, Durham, NC
MATTHEW J. WEISS, MD • Department of Surgery, Johns Hopkins Hospital, Baltimore, MD
PATRICIA WORTHINGTON, RN, MSN, CNSN • Department of Nursing, Thomas Jefferson
   University Hospital, Philadelphia, PA
RONIT ZILBERBOIM, PhD • Lonza Inc., Annandale, NJ
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Chapter 1 / Perspective on DNIs                1

      I                 OVERVIEW
2   Part I/ Overview of Drug–Nutrient Interactions
Chapter 1 / Perspective on DNIs                                                            3

      1          A Perspective
                 on Drug–Nutrient Interactions

                 Joseph I. Boullata and Jacqueline R. Barber

    There are so many drugs available for use in the human condition, with continued
approval of new agents, and expanded indications for existing ones (1). Likewise spend-
ing on pharmaceuticals in the United States continues to increase by 10–15% each year,
driven by increased utilization as well as increased cost per prescription (1). According
to a recent report, close to $141 billion of the estimated $1.4 trillion spent on health care
annually in the United States are accounted for by prescription drugs (2). Beyond pre-
scription medication, the wide availability of over-the-counter (OTC) pharmaceuticals
and dietary supplements together with the increasing emphasis on self-care among people
further increases consumption patterns of pharmacologically active substances. Recent
estimates are that about 80% of Americans use medication, whether prescription, OTC,
or dietary supplement products (3).
    Although dietary intake may not be recognized in similar terms of increasing discov-
eries, it should be recognized that food intake habits have changed along with advances
in nutrition and food sciences (4–6). Furthermore, our understanding of food compo-
nents included in the diet, whether nutrients or phytochemicals, has expanded (7,8).
This makes for an ever-widening potential for interactions between drugs and food, food
components, or specific nutrients. The potential for interactions becomes that much more
complex when patients with any underlying alteration in nutritional status are included.
The working definition of a drug–nutrient interaction (DNI) used throughout this volume
is that which results from a physical, chemical, physiologic, or pathophysiologic relation-
ship between a drug and a nutrient, multiple nutrients, or food in general. The interaction
is considered significant from a clinical perspective if therapeutic response is altered or
nutritional status is compromised.
    The potential number of interactions and permutations seems infinite. But it remains
unclear what proportion of these have actually been identified, and more to the point,
what number of the identified subset may be considered clinically significant. Clearly,
if one is not looking for a DNI, one will not find it. For those interested in identifying
specific interactions, a number of books over the years have dedicated some or all pages
to DNIs (5,9–29). Some lists of DNIs are so brief they seem to question the legitimacy
of the topic, others are so extensive one wonders how an interaction could ever be
                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
4                                             Part I/ Overview of Drug–Nutrient Interactions

avoided. With this mixed message, many clinicians simply discount the relevance of
DNIs to their practice. A recent survey of health care providers found their knowledge
of common DNIs to be wanting (30). This may in part explain why so few health care
providers provide DNI counseling to the majority of their patients (31). These findings
occur at a time when regulatory agencies expect DNIs to be addressed by clinicians in
institutionalized settings. What is needed is a rational approach to evaluating the scien-
tific basis and clinical relevance of existing DNIs to allow for appropriate recommenda-
tions. At the same time, this approach should set up a framework on which to build a
database for the many interactions yet to be identified, evaluated, and documented.
Although much has been done over the years, much more still needs to be accomplished.

   Through the ages, the use of food combinations or the addition of medicinal remedies
to food were employed to preserve health or to manage disorders. Time has not slowed
down either our penchant for food or the advancement of therapies used to manage
disease. But more important than a historic review of the entire topic, is the evolution in
relative importance placed on clinically relevant DNIs.
   That disease and therapy could precipitate malnutrition was barely mentioned in a
lengthy clinical review on nutritional assessment many years ago (32). A few decades
later, the only clinically recognized DNIs were the more obvious intraluminal interac-
tions between drug and food (33). It was still several years until the first major review
recognizing the impact of food on drug absorption was published, finally stimulating
clinical interest (34). As a result, any identified interactions between a drug and food were
then treated with caution. The appreciation that not all interactions were clinically rel-
evant developed more slowly. Even then, the idea that clinically relevant DNIs may
involve more than simply physical interactions between food and drug also evolved
slowly. This limited clinical focus occurred despite much earlier work on the impact of
specific nutrients on drug metabolism (35) and the effect of drugs on nutrient metabolism
(36,37). At about the same time, the overlap of heredity on the interaction between drugs
and nutrients was recognized (38), and the effects of nutritional status on drugs began to
be explored as well (39,40). Over the intervening decades, DNIs have been studied and
discussed more formally, and presented in practical formats.
   Dr. Daphne A. Roe was once referred to as the founder and “godmother” of the DNI
issue (41). This noted physician spent a good portion of her tremendous professional
energies in the arena of DNIs. She clearly understood that it was the responsibility of all
clinicians to understand DNIs, and provided guidelines that included clinical aspects of
DNIs. Besides contributing to the primary literature (42–46), she authored handbooks
(10,20,21) and texts (13,14,17) on the subject. She also served as the editor of a journal
dedicated to the topic—Drug–Nutrient Interactions: A Journal of Research in Nutrition
Pharmacology and Toxicology (Drug–Nutr Interact), first published in 1982. A quick
review of the periodical for its topics and authors reveal the breadth of original research
activity and the quality of investigators in the field of nutritional pharmacology, many of
whom remained active. They represented departments of nutrition, food science, and
pharmacology in schools of medicine, pharmacy, and varied universities. The studies in
the journal were supported by a variety of government and industry sponsors, as well as
Chapter 1 / Perspective on DNIs                                                            5

individual academic institutions, in the United States and abroad. The contents of some
of the published papers set the stage for the current understanding of DNIs. There were
studies that teased apart mechanisms, and involved human subjects as well as animal
models. Negative studies were included to allow for clarification of issues. Although
papers seemed to answer some of the questions of the day, they certainly opened the doors
to further questions. From a clinical perspective, the work published in Drug–Nutr Interact
began to scratch the surface. Some of the studied drugs are no longer in use, but considering
the number of drugs that enter the marketplace each year, so many more have yet to be
evaluated for their DNI potential. In fact, in recent years the re-emergence of herbal
remedies and complex dietary supplements have increased awareness of, if not identified
weaknesses in, DNIs and their relevance. Much of this type of literature is now published
across various disciplines in the clinical and scientific journals of food science, medicine,
nutrition, pharmacology, and pharmacy.
    But much is left undone or unstudied. Each potential DNI needs to be investigated, and
those with clinical relevance need to be documented by clinicians, and examined mecha-
nistically by researchers. From a practical standpoint, the focus of surveillance should be
on the most commonly used chronic medications, particularly those that influence homeo-
stasis, having a narrow therapeutic index, and active metabolites, in populations at greatest
risk. High-risk populations would include the elderly, the critically ill, and those requir-
ing nutrition support. We need to be able to identify additional factors (e.g., gender,
genetics, other disease states, etc.) and then predict relevant interactions. Genetic mark-
ers of susceptibility and outcome need to be explored further. Research goals considered
appropriate at an international conference in 1984 are still relevant in 2004 (46). They
included reporting DNIs, understanding their cause, predicting likelihood of outcomes,
assessing subpopulation risk factors, and educating health care professionals.
    Given the early descriptions of interactions as impacting predominantly on absorption,
it is not difficult to understand how many clinicians have come to dismiss or trivialize all
but a few of the documented or potential interactions. Another barrier to overcome is the
lack of consideration given to nutrients as being “drug-like.” Each nutrient is an organic
structure or inorganic element, with unique properties, that require absorption, distribu-
tion, metabolism, and elimination from the body, and in fact elicit a dose-related physi-
ologic response from that body following administration. An interaction could potentially
occur at any point in nutrient disposition or effect.
    A recent approach based on scientific rigor could lead to a more comprehensive
examination of the broad range of DNIs (47). It specifically recognizes that more research
and clinically relevant information about DNIs is needed (47). Toward a rational approach
to generating and presenting data on DNIs, it seems reasonable to classify existing DNIs,
generate new data, recognize the complexity of individual interactions, appreciate the
breadth of the topic, and identify sources for clinical application.

3.1. Classification
   The classification of DNIs can be approached in a variety of ways—by drug, by
nutrient, by patient type, by outcome (clinical manifestations), by mechanism (chemical
or physiologic), or by location (ex vivo, gastrointestinal [GI] tract, circulation, and site
6                                              Part I/ Overview of Drug–Nutrient Interactions

of effect). A classification system based on the location and mechanism of an interaction,
with both an identified precipitating factor and an object of the interaction may help to
more easily design management strategies, and focus research efforts. Such a classifica-
tion system for clinically identified DNIs as recently described (47) could fit into a single,
broad, and inclusive approach (Table 1). Such an approach would allow DNIs to be
described or examined based on five general categories:
 1.   The impact of nutritional status on drug disposition and effect.
 2.   The impact of food on drug disposition and effect.
 3.   The impact of specific nutrients on drug disposition and effect.
 4.   The impact of drugs on nutritional status.
 5.   The impact of drugs on the disposition and effect of specific nutrients.
   Within each of the five categories, a specific precipitating factor would have a defined
location and/or mechanism of interaction with the object that is affected by the interac-
tion. Keep in mind that the precipitating factor could be multifaceted, including the
interplay of disease and genotype.

3.2. Mechanisms
   Why certain drugs and nutrients interact with each other and not with others, relates to
physicochemical factors of the medication, food or nutrient, as well as to individual physi-
ology whether normal or disordered. But the clinical consequences often relate to altered
disposition and/or effect. Disposition includes steps that influence bioavailability,
distribution, metabolism, and excretion. Effect refers to pharmacological or physiological
consequences of a drug or nutrient interacting directly or indirectly with cellular targets.
   Malnutrition, from starvation to obesity, can influence drug absorption, distribution,
elimination, and effect. Food in general, the type of meal, a specific food, or even non-
nutritive food constituents can impact on the absorption, elimination, and effect of vari-
ous drugs. At the level of the GI tract, interactions may be due to physicochemical
reactions, as well as altered enzyme or transporter function. Nutrients found in food, or
those delivered in pharmaceutical dosage forms can interact with drugs as well. The
complexity of enteral and parenteral nutrition regimens and the patients who require them
creates opportunity for numerous interactions. This would include specific physico-
chemical reactions for ex vivo interactions involving the mixture of medication with food
or with nutrition support products. Mechanistically, DNIs may occur ex vivo as reactions
between drugs and nutrients in a delivery vehicle, at the site of drug and nutrient absorp-
tion to alter bioavailability, and systemically in drug or nutrient distribution, storage,
metabolism, or elimination (47). Specific drugs may alter nutrient intake, absorption,
storage, metabolism, and excretion. Non-nutrient agents (herbals and other dietary supple-
ments) have the same potential to alter nutritional status and nutrient disposition. Sys-
temic interactions may involve effects on distribution, biotransformation, elimination, or
organ, tissue, cell membrane, or subcellular function.

3.3. Impact of Nutritional Status and Food Intake on Medications
   Both protein-calorie malnutrition and obesity are known to influence drug disposition
and effect (48,49). Several micronutrients including riboflavin and ascorbic acid are
active components in microsomal enzyme systems used for drug metabolism with capac-
Chapter 1 / Perspective on DNIs                                                             7

Table 1
Approach to Drug–Nutrient Interactions
 Precipitating        Object                                        Clinical
    Factor        of Interaction      Scientific Basis         Management Strategy
Altered              Drug           Identify mechanism       Aim to minimize treatment
  nutritional status                                           failure or drug toxicity
Food or food         Drug           Identify mechanism       Aim to minimize treatment
  component                           and location             failure or drug toxicity
Nutrient             Drug           Identify mechanism       Aim to minimize treatment
                                      and location             failure or drug toxicity
Drug                Nutritional     Identify mechanism       Aim to maintain or improve
                      status                                   nutritional status
Drug                Nutrient        Identify mechanism       Aim to maintain or improve
                                      and location              status of individual nutrient

ity reduced in deficiency (50,51). Although vitamin A deficits may slow drug metabolism
in animal models, this remains poorly defined in humans (52). However, it may not even
require a clinically apparent alteration in nutritional status for dietary changes to influ-
ence drug response (38), particularly when underlying gene polymorphism plays a role.
   The known polymorphism of methylenetetrahydrofolate reductase (MTHFR) can be
important in terms of determining appropriate nutrient dosing (vitamin B6, vitamin B12,
folic acid, riboflavin) (53,54). Genetic variants in vitamin metabolism can likely mean
more individualized requirements. It may also be important in terms of the drugs that
impact on the associated pathways. For example, methotrexate toxicity may be manifest
differently depending not only on folate status but also on MTHFR genotype (55). For
example, cases of hematologic toxicity associated with low-dose methotrexate as used
in rheumatoid arthritis patients have been reported. These occurred in patients not receiv-
ing folic acid. The reports describe serum folate (but not erythrocyte folate), but then
barely mention the issue of folic acid supplementation let alone genotype (56,57), despite
recommendations to include folic acid in methotrexate regimens (58). The value of folic
acid supplementation during treatment with methotrexate should be evaluated prospec-
tively while also taking MTHFR genotype into account.
   Meals, specific foods, or specific compounds in foods can impair drug absorption and
bioavailability (59). For example, carbohydrates may enhance, and protein may reduce
phenytoin absorption (60). Foods containing hydrolyzable or condensed tannins (e.g.,
black tea, coffee) can cause precipitation of medications (e.g., phenothiazines, tricyclic
antidepressants, propranolol, hydralazine, histamine receptor antagonists) even in
diluted form at intestinal pH (61). Drug metabolism is also influenced by the diet (62).
Use of drug cocktails (e.g., midazolam, caffeine, chlorzoxazone, and debrisoquin) and
metabolite ratios can help predict cytochrome P450 (CYP)-mediated interactions, includ-
8                                             Part I/ Overview of Drug–Nutrient Interactions

ing those posed by dietary supplements, while taking individual phenotype into account
(63). Supraphysiologic doses of the various vitamin E isoforms may play a role in drug
interactions (64).

3.4. Impact of Drugs on Nutritional Status
   The impact of drugs on nutritional status or on the status of a specific nutrient has been
well recognized (36,37,65,66). Many such realizations occurred as synthetic drug devel-
opment proliferated. Drugs can influence nutrient synthesis, absorption, distribution,
metabolism, and excretion. However, a few situations account for most clinically com-
mon nutrient depletions—when a drug causes significant anorexia or malabsorption,
when nutrients are involved in multiple pathways (e.g., folic acid, vitamin B6), or when
a drug, by its structure and function, is a vitamin antagonist (e.g., methotrexate). Even the
anti-vitamin effects of a medication may be due to one or more factors—reduced absorp-
tion or reduced conversion to active form, interference with vitamin-dependent path-
ways, or increased vitamin clearance (metabolism or excretion). These are each more
likely to occur when used chronically, and in patients with marginal nutritional status.
The biochemical or functional or clinical manifestation will depend on the degree of
deficit and the tissue compartment most affected. Stretching the definition would also
include drugs that could induce pancreatitis and thereby alter nutrient disposition. Of
course by implication, DNIs are assumed to play negative roles in patient outcome, but
some interactions can improve therapeutic outcome. In fact, the action of certain drugs
(e.g., warfarin) are by their very nature the result of a DNI.
   There may be as yet unrecognized adverse nutritional effects to a given drug. Recog-
nized drug effects can include a reduction in appetite or absorption, alteration of nutrient
metabolism, and increased urinary losses, whether used for a short or longer duration.
These only account for drug-related factors; the patient variables are also important.
These might include altered physiological nutrient requirements, a marginal diet, malab-
sorption, a chronic or catabolic disease, altered organ function, concomitant ingested
substances (drugs, dietary supplements, drugs of abuse) or environmental exposures (or
lack of ultraviolet light in the case of vitamin D), and pharmacogenetic variability.
   The influence of drugs on nutritional status may begin with impeding the ability to
gather, prepare, and ingest food. The next logical step of interference would be nutrient
absorption, which was documented early in the case of mineral oil (67). This could occur
because of physicochemical interactions within the lumen as well as via mucosal damage,
altered bile salt availability, or pancreatic exocrine function (68,69).
   Micronutrient deficits need to be examined along a spectrum from normal status to
overt classic deficiencies. For example, vitamin B6 deficits following treatment with
isoniazid (iso-nicotinic acid hydrazide) may manifest as neuropathic, anemic, or pella-
grous findings. Quite a number of drugs are known to alter vitamin B6 status given the
reactivity of the compound (70). Folic acid deficits secondary to phenytoin or methotr-
exate therapy may present with hypersegmented neutrophils, anemia, GI symptoms, and
weight loss. Several drug groups impact on vitamin B12 status by reducing absorption
(e.g., biguanides, bile acid sequestrants, proton-pump inhibitors), or inhibiting coenzyme
synthesis (nitrous oxide). These losses would be expected to occur over time eventually
leading to classic signs or symptoms of deficiency, but should be identified (or better yet
prevented) long before that degree of deficit has been reached. Theophylline, for example,
Chapter 1 / Perspective on DNIs                                                             9

is a pyridoxal kinase antagonist at therapeutic concentrations that could induce vitamin B6
deficits. It is possible that some patients taking the drug chronically may require vitamin
B6 supplementation to limit nervous system side effects, particularly tremor seen at
therapeutic concentrations (71).
    The cause and even the diagnosis of drug-induced vitamin D deficiency are likely often
overlooked. Given the complexities of vitamin D formation, activation, and metabolism,
not to mention polymorphism of the vitamin D receptor, drugs can interfere with vitamin
D status at several levels. OTC sunscreen products that provide a barrier to ultraviolet
light may reduce vitamin D formation in the skin. Bile acid sequestrants could reduce the
absorption of ingested vitamin D. Mineral oil and cholestryramine can reduce absorption
of vitamin D (and vitamin A) by acting as a solvent or by binding needed bile salts. This
is unlikely to lead to overt clinical deficits in vitamin A replete patients. Hepatic enzyme
inducers (e.g., phenobarbital, phenytoin, carbamazepine) could accelerate vitamin D
metabolism to inactive forms, among other effects, and otherwise result in low levels of
the active hormone. Regimens of broad-spectrum antibiotics may reduce intestinal floral
production of vitamin K2, although this is unlikely to lead to clinical deficits given the
minor role that this source of the vitamin plays in humans. However, pharmacological
doses of vitamin E can induce manifestations of vitamin K deficiency (72).
    Other potential interactions have not yet been well evaluated. For example, the initial
steps of vitamin E metabolism requires the CYP enzyme system, although metabolic
rates for each individual tocopherol and tocotrienol may differ (73,74). Inhibition or
induction of these pathways by drugs, including ethanol, could alter the clearance of
vitamin E forms or vitamin E status. Ethanol competes with retinol at a common initial
step in their metabolism, while increasing CYP activity, both of which create deficits of
retinoic acid, which in turn may account for ethanol-induced hepatic injury (75).
    Mineral status can also be influenced by medications. This relates both to macrominerals
(electrolytes) and microminerals. Consider, for example, the drug-induced syndrome of
inappropriate antidiuretic hormone secretion leading to hyponatremia. The antidepres-
sants have been reported to be one cause (76). This is especially true for the serotonin
reuptake inhibitors (77), although unlikely to be linked to CYP genotype (78). Diuretics
can cause true sodium depletion, as well as potassium losses. Laxative abuse and high-
dose corticosteroids may also cause hypokalemia (79,80). Aminoglycosides and ampho-
tericin B can also induce hypokalemia. Alcohol abuse leads to depletion of magnesium
stores. Neomycin and colchicine can induce intestinal malabsorption of calcium (81).
The proton pump inhibitor lansoprazole, used for significant gastroesophageal reflux
disease, may cause severe symptomatic hypocalcemia (82).
    Antinutrient, metabolic effects of a drug are typically acutely manifest (e.g., warfarin,
isoniazid), whereas those that interfere with intake, absorption, or clearance may take
longer to develop (e.g., cholestyramine, diuretics). If not being looked for, it is easy to
see how few clinicians recognize the importance of DNIs. Although the use of
cholestyramine may reduce vitamin absorption (e.g., folic acid, vitamin D), clinically
significant nutritional deficits may not occur in the nutrient-replete patient with adequate
intake. This is not to say it will not occur in a patient with marginal status or poor intake.
The point being that a clinically significant outcome is patient-specific, not necessarily
just drug-specific. Anecdotally, patients with the best adherence to therapeutic regimens
are those more likely to develop nutrient deficits. A complex case of drug-induced
10                                           Part I/ Overview of Drug–Nutrient Interactions

nutrient deficits leading to disease provides the opportunity to explain the cause (83).
It is interesting that few would question the value of providing pyridoxine therapy phar-
macologically to patients receiving isoniazid, for example, but many would consider it
strange to evaluate similar strategies for other medications that pose risks to nutritional
status (e.g., folic acid to patients receiving phenytoin).
    Although some of these interactions may be reasonably well recognized today, the
impact of medications on subclinical states of nutrient deficit may not be. The use of
analytic laboratory techniques to identify functional deficits may be valuable in assessing
the impact of a drug on nutritional status (45). The balance between requirements and
supply determines an individual’s nutrient status. Although nutrient requirements vary
with age, gender, and health status, the supply of nutrients is determined by food habits,
dietary restrictions, socioeconomic status, food processing and preparation, among other
factors. Recent surveys indicate marginal nutrient status in high-risk groups even if using
supplements (84). The poor ability of many clinicians to identify micronutrient defi-
ciency, whether clinically obvious or not, may limit the wider recognition of drug-induced
nutritional deficits. A nutritionally focused patient history and physical exam is important
in order to correctly identify nutrient deficits and differentiate them from the “usual
suspects” (85,86).

3.5. Adverse Drug Effects Following Nutrient Losses
   The idea that some adverse effects of medications are directly related to their influence
on nutrient status is not new. Several examples have already been described in the pre-
vious section. In other words, adverse effects of medication may occur through an alter-
ation of nutrient status.
   So, drug-induced nutritional deficits may be considered as a subclass of adverse drug
effects, whether identified as dose-related, duration-related, or idiosyncratic in nature.
For example, valproic acid hepatotoxicity, teratogenicity, and antifolate activity may
each be related by a common mechanism involving drug-induced alteration in the methion-
ine cycle (87). Management through nutrient replacement may not always prove correc-
tive. Nucleoside reverse transcriptase inhibitor-induced hepatotoxicity may be partly and
indirectly related to nutrient status, but a nutrient supplementation regime will not nec-
essarily improve the clinical manifestations (88). Also, nonsteroidal anti-inflammatory
drugs can irritate the GI tract leading to blood and iron loss, fluid and sodium retention
with weight gain, and possibly hyperkalemia—all of which are considered as drug-
induced nutritional effects.
   Antiepileptic agents are likely to alter the status of several nutrients, including folic
acid and biotin. The interaction between folate and phenytoin has been examined little
by little over time (89–93). Our understanding of this two-way interaction is still not
sufficient to assure a consistent management approach. Epileptic patients receiving
anticonvulsants, especially individuals with a specific MTHFR mutation, may have a
higher folate requirement based on homocysteine levels (94). Carbamazepine, among
other agents, can reduce the GI absorption of biotin and increase its metabolic clearance
(95,96). The metabolic consequences may be a reduced clearance of endogenous com-
pounds that are known to be neurotoxic. This could play a role in the adverse effects of
carbamazepine (96). Exploring the possibility that drug effects may have a nutritional
basis allowed someone to establish that the teratogenic effects of D-penicillamine were
likely related to copper deficits (97).
Chapter 1 / Perspective on DNIs                                                          11

   Bone marrow hypoplasia seen in severe malnutrition includes an anemia that responds
specifically to riboflavin administration. This appears due to secondary adrenal failure
or an indirect effect on erythropoeitin production or release (98,99). This could possibly
be one mechanism to explain how drugs might induce erythroid hypoplasia or aplastic
   The previous discussion of an approach to DNIs included brief reference to a small
number of examples. The story of a single nutrient in more depth may be informative.

   Vitamin C is a required nutrient for humans and other primates, as well as for the
guinea pig, each of which is unable to synthesize the molecule. With its own absorption,
distribution, and elimination now reasonably well described, ascorbic acid’s physiologi-
cal roles continue to be explored. It is an essential cofactor in numerous biochemical
reactions, including the indirect provision of electrons to enzymes, which require pros-
thetic metal ions in reduced form for their activity. Although rare, cases of the classic
deficiency state, scurvy, continue to be reported (85,86). Deficits of ascorbic acid in the
absence of scurvy are much more common, however, existing in close to half of elderly
hospital admissions (100). In addition to reduced intakes, some people regularly con-
sume vitamin C supplements above the current Recommended Dietary Allowance. This
diversity in vitamin C status is important because ascorbic acid is involved in drug
disposition and effect, and may itself be influenced by drugs. What follows is an overview
of these findings, which also highlight some of the confounding factors that impact on
any potential interactions. Much remains to be unraveled in the complexity of interac-
tions involving just this single nutrient. The same can be said for others and for nutrient
combinations and varied food matrices as seen in the clinical situation.

4.1. Role in Drug Metabolism
   Ascorbic acid’s role in drug metabolism was recognized early when vitamin C defi-
ciency was shown to impair pentobarbital metabolism and prolong its effect in a guinea
pig model (35). Antipyrine and caffeine are additional markers often used in studies of
hepatic drug metabolism. Antipyrine half-life also increases in guinea pigs with vitamin
C depletion (101). Although a change in half-life may also be a consequence of altered
volume of distribution, drug half-life was often used alone as a marker of clearance in
these older studies. Repletion of vitamin C in this model returned drug half-lives back to
normal (101). In a set of depletion–repletion studies, ascorbic acid did not appear to
influence antipyrine clearance in a primate model (102).
   A chronically vitamin C-deficient diet resulted in lower clearance and longer half-
lives of caffeine in a young group of adult guinea pigs (103). This was associated specifi-
cally with hepatic microsomal metabolism of these drugs, although not consistent with
ascorbic acid possessing a direct cofactor role (51) and recognized as likely influencing
the activity of select CYP isoenzymes (104). These reductions in drug metabolism were
also found to occur in subclinical states of deficit (105). The effect of vitamin C deficits
is most pronounced as hepatic concentrations fall below 30% of normal (106). The
activity of several hepatic enzymes is reduced in guinea pigs without scurvy but never-
12                                            Part I/ Overview of Drug–Nutrient Interactions

theless deficient in the vitamin (107). Although they help to identify mechanisms, find-
ings from animal models are not necessarily relevant to the clinical situation. The half-
life of caffeine in the guinea pig is about 10 h compared to about 5 h in man, and even
less in rodents. Conversely, the half-life of antipyrine is longer in humans (~10 h) than
it is in the guinea pig (~2 h). Assuming that these differences relate predominantly to
clearance, and not to differences in volumes of distribution, they may be accounted for
by variability in the population, density, and activity of the various CYP enzymes. Of
course, interspecies differences do occur, and some data has since been derived in hu-
    Similar findings in humans have been reported using antipyrine, whose low clearance
in patients with poor vitamin C status increased following vitamin C repletion
(100,108,109). This was demonstrated particularly in those elderly patients with sub-
clinical deficiency, but not in those without any obvious vitamin C deficits (100). These
findings have not always been confirmed in controlled human depletion trials, which may
be explained in part by different responses to acute compared with chronic deficits
(110,111). Chronic deficits and long-term repletion studies support the alteration in
antipyrine clearance with vitamin C status (109).
   Given the wide use of both vitamin C supplements and vitamin C-enriched food
products, patients may more commonly consume amounts of ascorbic acid above the
current dietary recommendations. This pharmacologic dosing of ascorbic acid may have
an impact on drug metabolism as well. In a guinea pig model, the chronic administration
of high-dose ascorbic acid significantly increased the elimination of caffeine compared
to the normal vitamin C group with an accompanying half-life reduction (103). Interest-
ingly, this was best seen in younger but not in older animals (103). Hepatic enzyme
activity is increased when large doses of ascorbic acid are administered above that in a
normal diet (107). High ascorbic acid levels, or vitamin C status in general, in part
differentiates the effect of age on caffeine pharmacokinetics. In a rodent model, large
ascorbic acid doses reduced hepatic, but not lung, CYP1A1 gene expression induced by
cigarette smoke exposure (112). In ascorbic acid-depleted but asymptomatic monkeys,
there was no change in antipyrine clearance compared with the repleted state except in
those further supplemented with isoascorbic acid (an isomer with similar redox potential)
in which clearance increased significantly (102).
   The limited findings on drug metabolism in humans appear as varied following ascor-
bic acid supplementation as with vitamin C deficits. Human studies have found that doses
of up to 1–4.8 g daily for 7 or more days may either increase or have no effect on antipyrine
clearance (113,114). At an ascorbic acid dose of 300–4800 mg daily for 1–2 wk there was
no influence on antipyrine clearance following a single oral dose (113). Ascorbic acid did
not affect the pharmacokinetics of antipyrine in elderly men (115). Again, the chronicity
of supplementation may play a role. Chronic consumption (12 mo) of ascorbic acid 500
mg daily did increase elimination of antipyrine in hypercholesterolemic patients, but the
variability in total body clearance effect was considerable (109). What determined the
variability—age, gender, genetics, dose—remains unclear. It should be kept in mind that
these human studies did not evaluate confounding factors such as ascorbic acid levels,
genotypic differences in CYP isoenzymes, or other medications.
Chapter 1 / Perspective on DNIs                                                               13

   Based on this discussion, it can be appreciated that vitamin C can potentially influence
the disposition or action of medications in clinical use. Although these involve ascorbic
acid’s role in metabolism, the vitamin may also potentially influence drug absorption,
distribution, and excretion. The interactions are not necessarily detrimental in all cases.
Conversely, drugs can influence ascorbic acid status as evaluated predominantly by static
tests (e.g., total body pool, tissue or fluid concentrations) rather than functional tests (e.g.,
enzyme activity).

4.2. Influence of Vitamin C on Drug Disposition
   By way of example, patients are known to ingest large doses of vitamins in attempts
to prevent adverse effects from chemotherapeutic agents. In vitro data suggest that vita-
min C at different concentrations may alter cytotoxicity of doxorubicin in several cell
lines (116). Evaluation of human lymphocytes indicate that ascorbic acid may reduce the
number of chromosomal aberrations caused by cisplatin (117). Ascorbic acid at a low
concentration (0.1 mmol/L) induces oxidative stress in platelets similar to the effect of
cisplatin, however, at higher concentrations (3 mmol/L), vitamin C had a protective effect
on cisplatin-induced oxidative stress (118). However, in vivo data from animal models
suggest that high-dose ascorbic acid does not improve and may worsen cisplatin-induced
nephrotoxicity and genotoxicity (119).
   Beyond chemotherapeutic agents, ascorbic acid may alter disposition or adverse effects
of other drugs. Modulation by vitamin C of a tobacco-specific nitrosamino to a less active
metabolite could reduce the toxin’s carcinogenic potential (120). Repeated doses of
ascorbic acid may reduce the impact of hepatotoxins like carbon tetrachloride (121).
Ascorbic acid may limit the potential for digoxin to induce lipid peroxidation, a means
of mediating drug toxicity (122). Lipid peroxidation induced by ceftizoxime was reduced
by ascorbic acid (123). Ascorbic acid has been used in the treatment of nucleoside reverse
transcriptase inhibitor-related mitochondrial toxicity (88). Consider how much of the
variability in adverse effects attributed to a medication may have a direct or indirect
nutritional explanation.
   In vitro findings cannot necessarily be extrapolated to in vivo or clinical situations.
Ascorbyl palmitate reversibly inhibits CYP3A4 in vitro, exhibiting strong competitive
inhibition of nifedipine oxidation, but this is not supported by in vivo data during a single-
dose study (124). Ascorbic acid is noted to increase the absorption and overall
bioavailability of co-trimoxazole, not otherwise predicted by in vitro study (125).
   The bioavailability of an oral contraceptive containing ethinyl estradiol and
levonorgestrel was not enhanced when 1 g ascorbic acid was taken 30 min prior in a group
of young women, despite the idea that competition for sulfation would allow for that to
occur (126). However, 1 g ascorbic acid daily has been reported to cause heavy break-
through bleeding during several cycles in a patient taking ethinyl estradiol/levonorgestrel,
that resolved when vitamin C was not used during a subsequent cycle, suggesting
increased drug clearance (127).
   Although high-dose “pretreatment” (1 g timed-release ascorbic acid, five times daily
for 2 wk) did not influence circulating lactate-pyruvate ratios or impaired intellectual
function following acute oral administration of ethanol (0.95 g/kg), it did increase serum
triglycerides and enhance ethanol clearance in the otherwise healthy volunteers (128).
There was significant variability in the degree of enhanced clearance (1–74% increase),
14                                           Part I/ Overview of Drug–Nutrient Interactions

whereas several subjects had slight decreases or no change at all in ethanol clearance.
This tended to support a previous finding of ascorbic acid-dependent ethanol oxidation
via catalase. The greatest increase in clearance occurred in those with the slowest clear-
ance during the placebo phase. The highest increase in clearance following ascorbic acid
pretreatment occurred in an Asian subject, leading to the suggestion of phenotypic con-
founding as well (as Asians are more likely to possess atypical forms of alcohol and
acetaldehyde dehydrogenase). Pharmacological doses of ascorbic acid are also reported
to reduce acute alcohol-induced hepatotoxicity (129).
   In terms of inducing metabolism of misonidazole, a radiosensitizing agent used with
radiation therapy, 2 g ascorbic acid daily for 2 wk in healthy humans did not compare to
1 wk of treatment with phenytoin or phenobarbital (130). Although phenytoin and phe-
nobarbital each induced misonidazole metabolism, thereby increasing total body clear-
ance and reducing area under the curve, ascorbic acid did not.
   Although 1 g of vitamin C may not be problematic, higher doses of ascorbic acid may
interfere with the activity of warfarin when taken together (131–133).

4.3. Influence of Drugs on Vitamin C Status
   It appears from an animal model that aspirin may influence ascorbic acid distribution
by inhibiting its uptake into leukocytes and hence result in an increased urinary excretion
of ascorbic acid (134). This is an example of a medication worsening the status of a
nutrient. Both aspirin and ethanol may reduce tissue ascorbic acid saturation (135).
Although speculative, the reduction in tissue saturation may occur in part by a change in
the function of ascorbic acid transporters or the expression of transporter genes. Oral
contraceptive users appear to have a more rapid turnover of ascorbic acid (136,137).
Cigarette use can worsen ascorbic acid status. Although it is known that tobacco smokers
have a higher metabolic turnover of vitamin C (138), the environmental exposure to
tobacco smoke may also reduce ascorbic acid concentrations in nonsmokers, including
children, even after adjusting for dietary intake (139,140).
   Additional human studies of DNIs involving ascorbic acid need to be undertaken,
while controlling for genetics, nutritional status, and other factors, in order to develop a
better handle on the clinical significance of identified interactions and to design appro-
priate recommendations.

5.1. Patient Care
    Minimizing adverse outcomes and maximizing benefits of medicines includes reduc-
ing the prevalence of DNIs. Although once limited predominantly to dietitians, it has
become the purview of other clinicians as well (e.g., pharmacists, nurses, and physi-
cians). In order to be competent in preventing or managing clinically significant DNIs,
it is necessary for clinicians to be able to recognize and identify them first. This comes
as part of a thorough assessment of a patient’s presenting history and physical examina-
tion. Examining patients with a chronic disorder often turns up interesting dietary habits
as well as patterns of medication use. Clinicians should not be content just knowing that
antidepressants may cause weight gain, diuretics may cause hypomagnesemia, or that
Chapter 1 / Perspective on DNIs                                                           15

poor anticoagulation with warfarin could result from changes in dietary vitamin K. Ques-
tions need to be posed by curious clinicians to identify the less well-known or as yet
unknown DNIs.
    Nutritional status of patients needs to be routinely evaluated, and if malnutrition is
identified, one of the questions that needs to be asked is whether it is drug-induced.
Similarly, if an alteration in the status of a specific nutrient or group of nutrients is
suspected, one should question the contribution of the patient’s drug regimen. If the
therapeutic effect of a drug is other than expected, whether subtherapeutic or toxic, the
question needs to be asked whether the effect is nutritional status-, diet-, food-, or nutri-
    One-on-one counseling with patients about DNIs needs to be focused and include
supporting patient education materials. Counseling materials and programs have been
developed (141). Patient-focused information on select DNIs is even made available by
the Clinical Center at the National Institutes of Health, based on the work of a task force
( More than just a list of drugs
and nutrients that interact, material can make targeted efforts at specific patient sub-
groups likely to be using many medications. The materials need to be available in all care
settings and to all health care providers. Adverse consequences of DNIs—reduced effi-
cacy, increased toxicity, altered nutritional status—do not discriminate by care setting.
Clearly, the issue of patient counseling on DNIs should cover all patients in acute, chronic,
or ambulatory care settings. Reporting of suspected cases of DNIs is still to be encouraged.
    Up until about the 1980s, what we knew about DNI causes, effects, and preventive
measures came mostly from observation, personal investigation, or reading the limited
literature—often largely anecdotal. The emergence of computer technology has allowed
for the creation of databases to explore these interactions. An early system of spread-
sheets took into account the specific attributes of DNIs such as those causing lactose
intolerance and flushing reactions (42).
    How can one assure safe use of drugs with respect to nutritional status? Identification
of risks is paramount to prevention or minimization of DNIs. Certainly, altered nutri-
tional status, chronic drug use, and age serve as risk factors for DNIs. In the same way
that every medication is expected to have adverse effects of one degree or another, it could
be expected that there are potential effects on nutritional status unless proved otherwise.
Patients may be at risk for drug-induced malnutrition (global or nutrient-specific) based
on genetics, age, poor diet, malabsorption, organ dysfunction, or substance abuse.
    Sources of answers include individual case reports, drug-surveillance reporting sys-
tems, and case-control and cohort studies. Some of these data are found in more conve-
nient summary format.

5.2. Resources for Point of Care
   Resources for information on DNIs are varied and continually evolving. Traditionally,
information could be accessed through research of references including but not limited
to textbooks, handbooks, journal articles (pharmacy, medicine, dietetics, nursing, and
nutrition literature have all been useful resources), as well as Joint Commission on
Accreditation of Health Care Organizations (JCAHO) manuals and publications. Assem-
bling information in this manner and adapting it for use in various settings could be time-
consuming. Along with these types of references, more commonplace are examples of
16                                            Part I/ Overview of Drug–Nutrient Interactions

nutrition and DNI screening programs incorporated into the hospital or health system
computer package(s). These computer programs promise the advantages of providing
more consistency while greatly streamlining the process of making the information more
readily available to clinicians and ultimately, to patients.
   Newer mechanisms for clinician-friendly, point-of-care resources include programs
that can be accessed via the internet or CD-ROM, and downloaded or installed into
personal digital assistants (PDAs), such as the PalmOS or Pocket PC-based devices. On
PDAs, they are carried along for immediate use during the course of clinical activities.
Two specific resources that offer various options in each of these categories are listed
in Table 2. Reference tools such as these offer the advantage of being updated regularly,
in some cases multiple times in the course of a calendar year, making it easier to remain
current with new data. Other internet-based resources include the various search engines,
Medline resources, Micromedex , listservs for clinical nutrition or hospital organiza-
tions, and web sites of related professional groups (JCAHO, American Society for
Parenteral and Enteral Nutrition [ASPEN], American Dietetic Association, American
Pharmacists Association, American Society of Health-System Pharmacists, American
Nurses Association).
   Finally, one should not underestimate the experience of colleagues and other institu-
tions and organizations when attempting to develop and refine programs of this nature.

5.3. JCAHO
   The JCAHO has defined the role of hospital clinicians in identifying and preventing
DNIs. The JCAHO requires a level of sophistication in documenting and managing these
DNIs in organized health care settings in the United States. Specifically, it is stipulated
that “patients are educated about potential drug-food interactions, and provided counsel-
ing on nutrition and modified diets” (142). Although it is mandated that patient education
regarding potential DNIs shall take place, it is not specifically described how this is to be
done within each organization. Rather, it is left up to the individual setting to assess the
needs of its patient population and resources of staff in order to design an appropriate plan.
Institutions vary greatly in the types of patients served, nature of drug and supportive
therapy delivered, and staff available to conduct this type of patient education. It is not
specifically delineated which health care providers are to be involved, although this
responsibility may typically involve physicians, dietitians, pharmacists, and often, the
primary nurse for the patient (143). Surveyors may also differ in emphasis placed on
evaluation of different programs. Information from various institutions that have recently
prepared for and undergone JCAHO review may be accessed through internet search
engines as well as via organizations such as ASPEN through their web site (www.nutri- and listserv services available to members. The current JCAHO accredita-
tion manual, their website (, and various other JCAHO publications may
also be helpful (144).
   Several approaches have been employed in the development of DNI education pro-
grams in hospital and health care settings in response to JCAHO stipulations that such
education for patients be implemented (145,146). One example of such an approach
includes targeting certain patient groups as being more likely predisposed to DNIs, such
as newly diagnosed diabetics, transplant patients receiving high-dose corticosteroids,
patients taking pancreatic enzymes, or other patient groups that may require specific
Chapter 1 / Perspective on DNIs                                                                          17

    Table 2
    Examples of Resources for Drug–Nutrient Interactions in Multiple Formats
     Resource        Handbook          CD-ROM         Palm/Pocket PC PDA           On-line Format
                                      (Windows)       (Software Programs)          (Subscription)
    FMIa                 YES             YES                    NO                        NO
    Lexi-Compb           YES             YES                    YES                       YES
       aFood-Medication   Interactions, website:
       bLexi-Comp: a series of specialty medical and drug-related databases that include drug–nutrient

    information, website:

and/or multiple pharmacotherapies, and so on. Another popular approach is to instead
target certain “high-risk” drugs, examples of which may include warfarin, monoamine
oxidase inhibitors, selected antibiotics, phenytoin, lithium, theophylline, digoxin,
alendronate, cyclosporine, lansoprazole, isoniazid, drugs that may interact with grape-
fruit juice, drugs significantly affected by meals and feeding, and other combinations that
may cause potentially dangerous interactions. Identification of target drugs within a
health care setting may largely be based on two factors: degree of risk associated with use
of certain drugs, and frequency of use within that facility or health care system. Additions
to the formulary would typically be reviewed for propensity to induce clinically relevant
DNIs. Specialty services may develop their own list of drugs that require counseling
about potential food and drug interactions in their respective patients.
   In most institutions, DNI education programs are, by nature, and in practice, interdis-
ciplinary, and as such, a team effort. Examples of responsibilities of individual depart-
ments may be assigned as follows (145,147–149):
 1. The pharmacy may generate a daily list of patients receiving drugs targeted for DNI
    attention through the use of the hospital computer system and patient medication profiles.
    Cautionary labels or stickers may be utilized to draw attention to such drugs in the
    patient’s chart, drug bin, or in the automated dispensing systems (e.g., Pyxis machine).
    Protocols for standardized medication administration times with relation to food may
    also be developed and implemented with the collaboration of nursing units. Pharmacy
    personnel may also be involved with instruction of patients using written materials as
    necessary with appropriate documentation in the patient’s medical record.
 2. Nutrition and food services can use the list generated by the pharmacy to make modifi-
    cations in diet choices and snacks in order to avoid certain DNIs. Dietitians may docu-
    ment changes, identify food restrictions for individual patients, and also provide patient
 3. Nursing activities related to addressing DNIs in hospitalized patients often include
    maintaining readily available resources for patient instruction and information, checking
    for alerts or warnings related to drug therapy and possible interactions with foods, and
    assuring that appropriate standardized protocols for administration and timing of medi-
    cations in relation to food and meals or nutrition support regimens are employed.
 4. Outpatient care providers in various settings may also be involved in providing informa-
    tion and instruction to patients receiving prescriptions or therapy involving target drugs.
18                                             Part I/ Overview of Drug–Nutrient Interactions

   Experience has shown that JCAHO historically places significant emphasis on deter-
mining the existence of the DNI patient education program in a form appropriate to the
setting, and that such activities are documented in the patient care record by the health care
providers involved. This information must be made available for inspection on request.
Although these points continue to be significant in audits, it is important to recognize that
the specific focus during the survey is continually evolving, and subject to the discretion
of the specific team of surveyors. The intent of surveyors in reviewing DNI practices within
an institution is to ascertain that predetermined standards have been developed, a program
for addressing DNIs is in place, and that resultant activities to meet those standards are
employed, documented, re-evaluated on a regular basis, and improvements incorporated
as indicated. In summary, the JCAHO wants to know how and why the institution or health
system arrived at its existing policy regarding DNIs, how well the institution is meeting its
defined objectives, and the current status of the overall plan (150,151).

5.4. The Next Step?
   Frankly, the number of professionals interested in this area with qualifications in both
nutrition and pharmacotherapeutics has been limited, given so many other opportunities
for these individuals. And given the potential scope of the problem, it could be viewed
from a public health perspective that more should be done. Identifying cases in practice
is even difficult when one considers that there is no one person looking specifically at
nutritional aspects of drug use or vice versa. Dietitians may take very good diet histories,
whereas pharmacists may do the same with drug usage, taking into account prescription,
OTC, and supplement intake. However, whether a particular clinical manifestation as
observed by the physician is integrated with the diet or drug history to conclude the
possibility of a DNI seems infrequent. This may account for the poor documentation of
DNIs in practice and the limited research in the area. What about the vast majority of the
medication-consuming public seen rarely if at all by a dietitian, infrequently by a phy-
sician, and for only limited visits with a pharmacist—many who are not attuned to the
potential for DNIs? Yet, it is this ability to identify a potential DNI that is required to set
off the signal for further study. A case report or case series may lead to a hypothesis that
can be tested. Several things could be tried to move the topic forward.
   An organized, technology-based system would likely perform better than observation
or voluntary case reporting alone. Surveillance data (e.g., Boston Drug Surveillance,
phase IV drug study, National Health and Nutrition Examination Survey) may be useful
for generating hypotheses as well by identifying poor drug outcomes by nutritional
association, or poor nutritional status with drug intake. This may be more economically
acceptable than performing DNI screening as part of the premarket drug safety process.
But to make this work requires clinicians who recognize the potential for DNIs and who
evaluate that potential with each contact with a patient. A scoring system to determine
the probability that an adverse outcome is related to a DNI could be developed based in
part on the Naranjo criteria for estimating the probability of an adverse drug reaction
(152). Quantitative systems that examine GI physiology as it affects drug bioavailability
could be used to predict potential for DNIs (153). Predicting interactions based on small
intestine metabolic activity may become useful once genetic and gender variability is
taken into account. Correspondence analysis could also be used to identify agents or
Chapter 1 / Perspective on DNIs                                                                       19

patients at risk for significant DNIs (154). Pharmacogenomics technology could also be
potentially useful in predicting susceptibility to DNIs (155). Much work needs to be done
with our colleagues in biomedical informatics as it pertains to pharmacogenomics (156).
In the wake of the human genome project, a systematic understanding of the genes that
modulate drug response and more so the potential interplay of nutrients or nutritional
status on the phenotypes (enzymes, receptors, postreceptor signaling) and ultimately on
drug response (therapeutic or toxic) is important.

   The impact of drugs on nutritional status or the effect of nutrition on drugs is rarely
predicted from animal studies, and is not routinely assessed during the drug-approval
process. Ideally, every new drug should be evaluated for potential DNIs prior to marketing.
But given the poor likelihood of that occurring, clinicians should operate on the assumption
that any variability in drug response is the result of an interaction with nutritional status,
diet, food, or a nutrient unless proven otherwise. Variability from genetic, gender, and
age factors would also need to be taken into account. Similarly, any change in nutritional
status should be evaluated for drug-related causes.
   It would be difficult to study high-risk populations such as the elderly and those with
chronic conditions because of issues of consent or the time lapse involved in appreciating
nutritional deficiencies. A further constraint is the limited funding available for nutrition-
related research, particularly in this subject matter.
   Having an approach to DNIs may improve classification of old interactions and devel-
opment of an organized search for new ones, their mechanisms, and management options
to address them. However, what still remains critical is the clinician’s ability to recognize
poor outcome of drug therapy and search for potential causes including nutrition-related
factors. Just as important is the clinician’s ability to recognize alterations in nutritional
status, even single nutrient abnormalities, and seek drug-induced causes.
   DNIs will obviously depend on the drug and the nutrient, but will also depend on the
matrix of each, the model in which it is studied, the presence of disease or organ dysfunc-
tion, status of other nutrients, genetic polymorphism, and the like. Given all of this,
clinically useful data concerning all the potential DNIs have hardly yet been explored.
Additionally, research efforts to help refine existing recommendations are sorely needed.

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Chapter 1 / Perspective on DNIs                                                                          23

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Chapter 2 / Drug Disposition and Response                                                    27

    2            Drug Disposition and Response

                 Robert B. Raffa

   The basis for this book is that a drug–nutrient interaction (DNI) is the result of a
physical, chemical, physiologic, or pathophysiologic relationship between a drug and
nutrient(s)/food that is considered significant if the therapeutic response is altered adversely
or if the nutritional status is compromised. This chapter presents an overview of drug
disposition and drug action that forms the basis for understanding such adverse interactions.
   Pharmacokinetics is the term used to describe drug disposition, that is the absorption,
distribution, metabolism, and excretion of the drug. Pharmacodynamics is the term used
to describe drug action (i.e., its mechanism and effects).

   Pharmacokinetics is important for understanding or predicting the magnitude or duration
of an effect of a drug or nutrient. A substance can produce an effect only if it can reach its
target(s) in adequate concentration. Several factors can affect the absorption and distri-
bution of drugs and nutrients.

2.1. Absorption
   The route by which a substance is introduced into the body affects its pharmacokinet-
ics (1,2). Hence, a review of the major characteristics of the more common routes of
administration is warranted.
   Systemic routes of administration are those that deliver the substance with the intent
of producing a systemic (on the system) effect, rather than a local effect on, for example,
the skin. A subdivision of systemic route of administration is parenteral, which refers to
systemic routes other than oral, sublingual, buccal, or rectal, which are termed alimentary
routes. Oral administration is generally the simplest, most convenient, safest (because of
slower onset of drug effect and ability to reverse a mistake), and often most economical
route of administration. Most drugs are well absorbed from the gastrointestinal (GI) tract.
The rate and extent of absorption is a function of the physiochemical properties of the
drug substance (e.g., hydrophilic, lipophilic), its formulation (e.g., tablet, capsule, liquid,

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
28                                            Part I / Overview of Drug–Nutrient Interactions

slow-release reservoir, or matrix), excipients, physiological environment (e.g., stomach
pH), and any metabolism in the gut wall. Alteration of any of these features that occurs,
for example, as a result of change in diet, lifestyle, age, or health status, can affect
absorption. Nutrients and foodstuffs can affect absorption by direct binding or by altering
the physiologic environment (e.g., pH of the stomach contents). The simple act of food
ingestion, or even its anticipation, can release digestive enzymes that inactivate certain
drugs, such as penicillins. The intravenous route of administration delivers drug sub-
stance directly into the bloodstream. With the exception of the portal circulation (see
later), the drug is then delivered to the heart and from there to the general circulation. The
intravenous route bypasses problems of absorption from the GI tract, allows for rapid
adjustment of dose to effect, can be used even if the patient is unconscious, and avoids
the “first-pass effect” (see later). Intra-arterial drug administration, although much less
common clinically than intravenous administration, is advantageous when infusion of a
high concentration into a specific target is desired, such as chemotherapeutic agents for
treatment of certain cancers and vasodilators for the treatment of Raynaud’s syndrome
(a condition characterized by excessive vasoconstriction, particularly affecting the dig-
its). Subcutaneous administration involves delivery of the drug into the tissue beneath the
skin for subsequent entry into the vasculature. Absorption following subcutaneous admin-
istration is generally rapid, depending on the perfusion of a particular site, and the rate of
absorption can be accelerated (e.g., by heating or vasodilators) or decelerated (e.g., by
cooling, vasoconstrictors, or slow-release formulations). Intramuscular administration is
generally rapid because of high vascularity and provides an opportunity for sustained-
release formulations such as oil suspensions. Inhalation provides one of the most rapid
routes of drug administration due to the large surface area and high vascularity of the lung.
Other systemic routes include intraperitoneal, which is particularly useful for the admin-
istration of drugs to small animals because it provides a rapid, convenient, and reproduc-
ible technique due to the warm, moist environment and extensive vascularity of the
peritoneum and the transdermal route, because of its convenience and control for extended
drug delivery.
   Systemic routes of administration provide an opportunity for drug and nutrient/food
interactions at several levels, including: the rate at which drug substance or nutrient is
available for absorption (e.g., dissolution rate, degree of ionization, adsorption, etc.); the
extent of plasma protein binding; and the rate or route of metabolism.
   Topical routes of administration—such as direct application to the skin or mucous
membranes—for the purpose of local action are not generally sites of interaction between
drugs and nutrients/food. A possible exception is the reduction of ultraviolet light expo-
sure by sunscreen lotions, thereby decreasing activation of vitamin D. However, if the
skin is damaged (such as in serious abrasions and burns) or if transmucosal passage is
significant, the drug does not remain localized to the site of application and administra-
tion is akin to systemic administration with the attendant opportunity for interaction.
   Direct application of drugs for localized effects to the eye (opthalmic administration),
ear (otic administration), nerves (intraneural administration), spinal cord (e.g., epidural
or intrathecal administration), or brain (e.g., intracerebroventricular administration) do
Chapter 2 / Drug Disposition and Response                                                  29

not often lead to significant nutrient/food interactions, but any substance that alters the
drug’s access to specialized compartments (e.g., through the blood–brain barrier [BBB])
will alter the magnitude or duration of the drug effect.
   The rate and extent of absorption is influenced by many factors related both to the
characteristics of the drug or nutrient substance and the particular characteristics of the
recipient at the time of administration (3). For example, the product formulation gener-
ally determines the rate of dissolution under specific physiological conditions, but these
conditions depend on the person’s state of health and other factors, such as diet. The
solubility of the administered substance, its dosage, and route of administration also
affect absorption.
   The absorption (and elimination) of substances generally follows either zero-order
kinetics, that is, a constant amount is absorbed (or eliminated) per unit time (Fig. 1A) or
first-order kinetics that is, a constant fraction is absorbed (or eliminated) per unit time
(Fig. 1B). Most of the currently used drugs follow first-order kinetics.

2.2. Distribution
    Whether a drug or nutrient is administered directly into the bloodstream, such as
intravenously, or indirectly via another route of administration, once in the bloodstream
it is subject to binding to plasma proteins, the extent of binding is dependent on the
physiochemical properties of the drug. Additionally, the drug or nutrient usually must
pass some biological barrier in order to reach its ultimate site of action. Because plasma-
protein binding is reversible and competitive, and there is a finite capacity for binding,
plasma-protein binding offers a potential site of drug and nutrient/food interaction.
   Due to their physicochemical characteristics, drug molecules (D) can form weak,
reversible physical and chemical bonds with proteins (P) such as albumin in plasma
according to D + P      DP (4). These drug–protein complexes (DP) have nothing to do
with the drug’s ultimate effect, but in some instances, can significantly influence the
magnitude or duration of the drug’s effect. This is because that protein-bound drug is
generally inactive at its site of action and, because of size exclusion, is less likely to
transverse the glomerulus into the kidney nephron and be excreted. Each drug binds to
plasma proteins to a different extent. Drugs that bind avidly with plasma proteins are
susceptible to interaction with other drugs and nutrients that bind to the same sites on
plasma proteins. This is because plasma-protein binding is saturable (i.e., there is a finite
number of such sites) and competition occurs among all substances that have affinity for
such sites. The transfer from the “bound” to the “free” state can result in a significant
change in effect magnitude or duration.
   The venous drainage system of the stomach and intestines differs from that of most
other organs in a way that has implications for drug effects. The venous drainage of most
organs goes directly to the heart, but venous drainage of the GI tract sends blood into the
portal circulation, which delivers blood to the liver (hepatic venous drainage then goes
to the heart). This is of clinical import because the liver is a site of active biotransforma-
30                                            Part I / Overview of Drug–Nutrient Interactions

Fig. 1. (A) An example of zero-order relationship. (B) An example of first-order relationship.

tion (discussed later) and potential for drug interaction. Biotransformation (drug metabo-
lism) in the liver can be extensive, accounting for more than 99% reduction of the parent
drug substance for some commonly used drugs. In some cases, this biotransformation
results in conversion of an inactive parent substance (prodrug) to its active metabolites.
More often, the metabolites are less active than the parent substance. Once through the
liver, the drug and metabolites follow the venous drainage to the heart and into the
systemic circulation. All subsequent pharmacokinetics is the same as for any other
systemically administered substance. Hence, the portal circulation introduces a special
influence on drug distribution during the first pass into the circulation (5). Drugs admin-
istered intravenously are not subjected to first-pass effect. Oral administration has the
highest first-pass effect.
   The extent of first-pass metabolism is an important consideration in drug design,
formulation, and dosage regimen. For drugs that undergo high first-pass metabolism,
small changes in the rate or extent of biotransformation can result in large changes in
systemic blood levels. Changes in biotransformation can result from changes in liver
function or from the effect of other drugs, nutrients, or food components on hepatic drug
metabolizing enzymes.
   Many drugs, because of their physicochemical properties, have only limited ability to
enter the brain. In general, the BBB restricts passage of macromolecules and substances
that are either too hydrophilic (water soluble) or too lipophilic (fat soluble). Nutrients and
other necessary substances can be actively transported across the BBB (6). The morpho-
logic basis for the BBB includes tight junctions between the epithelial cells lining the
brain capillaries and transport mechanisms that pump substances out of the brain.
Chapter 2 / Drug Disposition and Response                                                    31

   The permeability of the BBB depends on such factors as age, disease, and other
influences, including nutritional state. Plasma-protein binding is also a factor, because
drugs highly bound to plasma proteins are less able to traverse the BBB. Hence, drug
interaction at the level of plasma-protein binding can affect BBB passage.
   Biological membranes are matrices containing phospholipid bilayers, cholesterol,
proteins, and other constituents. Drugs can be transported around or through these mem-
branes, depending on the composition of the particular membrane. Some mechanisms of
drug transport are as follow (7):
    Passive diffusion. If a drug is sufficiently lipid soluble, it can diffuse down its concen-
    tration gradient (energy is not required, hence the diffusion is passive). For weak acids
    (HA H+ + A–) and weak bases (BH+ H+ + B), it is the un-ionized form (HA and B)
    that is more lipid soluble. Simple diffusion occurs according to Fick’s law:
                                           =   DA dC ,
                                        dt        dx
    where the flux of drug across a membrane is dependent on a diffusion constant (D), the
    surface area (A), and the drug concentration (C). This type of diffusion favors molecules
    in the uncharged form, and hence is a function of the pH of the environment at the
    membrane and the pKa of the drug according to relationships termed the Henderson-
    Hasselbach equations:

                                     pK a = pH+ log HA

    for weak acids and
                                    pK a = pH + log

    for weak bases. As a consequence, absorption of weak acids (e.g., aspirin) is favored over
    weak bases in the low pH of the stomach. However, the total amount of absorption is
    usually greater in the intestines due to the greater surface area. Conversely, an absorption
    of weak bases is favored in the small intestine (higher pH), and the acidic environment
    of the kidney nephrons favors (in a pH-dependent manner) excretion of weak bases.
    Filtration. Some vascular bed capillaries have pores or channels that allow the passage
    of low molecular weight substances, whether they are polar or nonpolar. Such capillaries
    serve as molecular sieves (filters) that exclude molecules larger than a certain size.
    Carrier-mediated (facilitated) diffusion. Transport of some substances across membranes,
    although by diffusion down a concentration gradient, is facilitated by membrane-asso-
    ciated molecules (carriers). This type of diffusion does not require energy and is gener-
    ally selective for molecules having specific structures or other recognized property. If the
    concentration of drug or nutrient exceeds the number of carriers, the process becomes
    saturated and further increase in drug or nutrient concentration will not increase the rate
    of their passage across the membrane.
32                                              Part I / Overview of Drug–Nutrient Interactions

     Active transport. Some molecules are transported across biological membranes against
     their concentration gradient. Transport in this direction—up a concentration gradient—is
     not favored thermodynamically and, hence, does not occur spontaneously. It requires
     input of energy, which is commonly supplied by coupled biochemical reactions that, for
     example convert adenosine 5'-triphosphate (ATP) to adenosine 3',5'-cyclic monophos-
     phate (catalyzed by Na+/K+-ATPase). Active transport is similar to carrier-mediated
     (facilitated) diffusion (discussed above) in that transport is mediated by a membrane-
     associated macromolecule (pump), it is saturable, and it is usually selective for certain
     drugs/nutrients (based on size, shape, or other characteristic). It differs in its requirement
     for energy and the ability to pump against a concentration gradient.
     Endocytosis. Some drugs or nutrients can be transported across biological membranes by
     becoming entrapped (in “pits”) and internalized (in “vesicles”) in varying degrees of
     selectivity. Sucrose and insulin can be internalized in such a manner.

   Because of the multiple barriers to absorption, the amount of drug that enters the
systemic circulation is less than the amount administered (with the exception of intrave-
nous administration). The proportion (fraction or percent) of an administered drug dose
that reaches the systemic circulation is the drug’s bioavailability. Other factors that affect
a drug’s bioavailability include the first-pass effect, solubility and stability, and the
formulation of the drug (including the quality control of its manufacture). Additionally,
a person’s dietary patterns, nutritional status, and state of health can affect a drug’s
   Multiple factors affect the distribution of substances in the body. Some are related to
the substance itself, such as its physical characteristics (e.g., size, solubility) and its
chemical characteristics (e.g., ability to form bonds with plasma proteins or other bio-
chemical substances). Other factors are related to the state of the physiological system,
such as concentration of plasma proteins, lipid content of barrier or target tissues, cardiac
output, capillary permeability in target or other tissues, and many others. Many of these
factors are a function of age, disease, or other influence.

2.3. Metabolism
    Drug/nutrient substances are often biotransformed (metabolized) to other substances
(metabolites) by a variety of biochemical reactions in a variety of locations throughout
the body (8). Almost all tissues can metabolize drugs, but the liver, GI tract, and lungs
(for gaseous anesthetics) are the major sites of drug metabolism of most drugs in humans.
The liver plays a predominant role in drug metabolism for two reasons: first, because of
its strategic location relative to the portal circulation, and second, because it contains high
levels of biochemical reactions that are capable of metabolizing foreign substances. In
general, but not always, metabolites are less active and more water soluble (which favors
excretion in the urine) than the parent substance. In some instances, active metabolites
are formed from inactive parent drugs, in which case the parent is termed a prodrug. The
most common chemical reactions that metabolize drugs or nutrients can conveniently
Chapter 2 / Drug Disposition and Response                                                 33

be categorized into two broad types: reactions that alter the basic chemical structure of
the parent molecule—phase 1 reactions—and reactions that result in attachment of some
endogenous substance to the parent molecule—phase 2 or conjugation reactions.
   Phase 1 type reactions often occur in the cytosol, mitochondria, and microsomes
(subcellular component containing membrane-associated enzymes on the smooth endo-
plasmic reticulum) of cells of the liver and other organs. Oxidation. Oxidation (e.g., the addition of oxygen or removal of hydrogen
from the parent molecule) is a common Phase 1 reaction. Microsomal oxidation is a major
mechanism of metabolism of many drugs and nutrients because the substances typically
have chemical structures that make them susceptible to oxidation reactions. There is an
extensive system (family) of enzymes that are capable of catalyzing oxidation reactions.
Primary components of this extensive system are cytochrome P450 (CYP) reductase and
the many isozymes of CYP. Examples of microsomal oxidation reactions are C-oxidation
or C-hydroxylation of aliphatic or aromatic groups, N- or O-dealkylation, N-oxidation or
N-hydroxylation, sulfoxide formation, deamination, and desulfuration. Examples of
nonmicrosomal enzymes having important roles in the metabolism of endogenous and
exogenous substances include: alcohol- and aldehyde-dehydrogenase; xanthine oxidase;
tyrosine hydroxylase; and monoamine oxidase.
   The family of CYP enzymes is particularly important in studying metabolism because
of the many drugs and nutrients that are metabolized by these enzymes and, in addition,
the potential for drug/nutrient interactions (9). For example, it is estimated that more than
90% of presently used drugs are metabolized by one or more of the CYP enzymes. Of the
most commonly used drugs, about 50% are metabolized by the CYP3A subfamily; about
25% by the CYP2D6 isozyme; about 15% by the CYP2C9 isozyme; and about 5% by the
CYP-1A2 isozyme. Because the enzymes are saturable, and can be induced or inhibited,
the potential for DNIs exist. Reduction. Reduction reactions (e.g., the addition of hydrogen or removal of
oxygen from the parent molecule) occur both in microsomal and nonmicrosomal frac-
tions of hepatic and other cells. Metabolism by reduction is less common than by oxidation
for presently used drugs. Examples of such reactions include nitro-, azo-, aldehyde-
ketone-, and quinone reduction. Hydrolysis. Hydrolysis-type reactions can occur in multiple locations through-
out the body, including the plasma. Examples of some nonmicrosomal hydrolases
include esterases, peptidases, and amidases.
   The coupling (conjugation) of an endogenous substance to a drug or nutrient molecule
typically alters its three-dimensional shape sufficiently to result in a decrease in biologi-
cal activity. Conjugation also typically results in an increase in water solubility of the
drug or nutrient, which decreases the amount that is reabsorbed through kidney tubules,
thereby enhancing the fraction that is excreted in the urine. Conjugation with glucose
(glucuronidation) is the most common conjugation reaction in humans. Other phase 2
reactions include glycine-, glutamate-, or glutathione-conjugation; N-acetylation (acetyl
34                                             Part I / Overview of Drug–Nutrient Interactions

coenzyme A as acetyl donor); O-, S-, or N-methylation (S-adenosylmethionine as methyl
donor); and sulfate or sulfanilate formation (3'-phosphoadenosine 5'-phosphosulfate as
the sulfate donor).
    It is common for a drug or nutrient to be metabolized through several biotransforma-
tion reactions, resulting in the production and the elimination of several or many metabo-
lites, each having its own pharmacokinetic and pharmacodynamic characteristics. It is
also common for a substance to undergo a phase 2 type reaction following a phase 1 type
reaction, but this sequence is not a requirement. It is possible for a phase 2 reaction to
precede a phase 1 reaction.
   Many of the enzymes involved in the biotransformation of drugs and nutrients can be
induced (increased in number or activity) or inhibited by a variety of chemical sub-
stances, including themselves and other drugs or nutrients (10). Induction results in an
enhanced metabolism of molecules that are biotransformed by affected pathways and
results in a decrease in the levels of parent molecule and increase in levels of metabolites.
Biological effect will be decreased if parent is more active than metabolites and increased
if parent is a prodrug. The opposite occurs with enzyme inhibition.
   Multiple factors can affect metabolism (11), including genetics, typically manifested
as polymorphisms; the chemical properties of the drug or nutrient, which determines the
susceptibility to the various types of metabolic reactions; the route of administration,
which affects the extent of the first-pass effect; dose, which can exceed the capacity of
substrates for conjugation reactions; diet, which can also affect the capacity of substrates
for conjugation reactions; age and disease, which can affect hepatic function; and still
2.4. Elimination
  The biological effects of exogenous substances are terminated by the combined pro-
cesses of redistribution, metabolism, and elimination (12). The major site of drug elimi-
nation in humans is the kidney. Several factors affect the rate and extent of elimination,
and accumulation occurs if the rate of absorption and distribution of a drug or nutrient
exceeds the rate of elimination.
   In humans, the kidney is the most common route for elimination of many drugs, partly
because the kidney receives about 20–25% of the cardiac output. Other sites include the
lungs (particularly for the gaseous anesthetics), and through the feces, and (usually to a
lesser, but no less important, extent) sweat, saliva, blood loss, vomit, breast milk, and so on.
   Size exclusion prevents plasma proteins—and drug molecules that are bound to them—
from passing through the glomerulus of a healthy kidney. The fate of molecules that pass
into the nephron depends on its physicochemical properties. Lipophilic drugs (or the
nonionized form of weak acids or bases) are more likely to be reabsorbed through the wall
of the nephron back into the circulation. Hydrophilic drugs (or the ionized form of weak
acids or bases) are more likely to be excreted in the urine. The pH dependence of ionization
Chapter 2 / Drug Disposition and Response                                                 35

is exploited clinically by adjusting the urine pH. Some substances are actively transported
across the wall of the nephron either into or out of the lumen of the nephron. Such transport
processes are generally saturable and are possible sites of DNIs.
    The rate of elimination of most drugs is described by first-order kinetics (i.e., expo-
nential decay) according to Ct = Coe–kt relating drug concentration (Ct) at time t to the
original concentration (Co). Other drugs are eliminated by zero-order (linear) kinetics. Co
is reduced by one-half in one half-life (t1/2). In the case of zero-order elimination, equal
amounts are eliminated each subsequent half-life. In the case of first-order elimination,
equal fractions are eliminated in each subsequent half-life. In either case, the half-life is
a function both of the drug and the conditions of the patient.
   Rate of elimination (mass/time) is equal to the concentration of drug (mass/volume)
times the clearance (volume/time). Clearance is the volume of a compartment (e.g.,
blood) per unit of time that is cleared of the drug due to elimination (e.g., metabolism and/
or excretion). The equation that relates renal plasma clearance (Cl), rate of excretion (Re),
drug concentration in plasma (Cp), and drug concentration in urine (Cu) is ClCp = CuRe.
   When a drug or nutrient is administered according to a fixed-interval schedule, the rate
of accumulation is predictable from the dose and half-life. For example, following the
repeated intravenous dosing of a drug having first-order elimination kinetics, the mean
drug concentration (Cm) can be estimated from the dose (D) and fraction of drug remaining
(F) by Cm = –D/ln F. The upper (Cmax) and lower (Cmin) bounds can be estimated by D/(1
– F) and FD/(1 – F), respectively. The actual clinical results depend on the patient’s
individual characteristics.
   In addition to the factors just cited, elimination can be accelerated by enzyme induc-
tion, increases in urine flow, or change in urine pH and can be slowed by renal impair-
ment, change in pH, or other factors.

   The mechanism of a substance’s action on biological tissue involves some modifica-
tion of or interaction with ongoing physiological processes. In some cases, the target is
foreign (e.g., bacteria or viruses) or aberrant (cancer cells). In other cases, the target is
part of normal physiology (e.g., enzymes or receptors). Mechanisms of action that are
shared or opposed by other drugs or nutrients can lead to interactions. Drug actions are
quantified and evaluated by dose–response curves.

3.1. Mechanisms of Action
  In the broadest sense, drug effects can be categorized into four major mechanisms (13).
They can kill invading organisms (e.g., most antibiotics or antivirals), they can kill
aberrant cells (e.g., many cancer chemotherapies), they can neutralize acids (antacids),
and they can modify physiological processes.
36                                            Part I / Overview of Drug–Nutrient Interactions

   Antibiotics and antivirals target biochemical processes of the invading organisms. For
example, penicillins, cephalosporins, carbapenems, and monobactams, which have
chemical structures that contain a -lactam ring, disrupt cell walls or inhibit their synthe-
sis. Sulfonamides and trimethoprim act on enzymatic pathways, resulting in the inhibi-
tion of folic acid synthesis. Aminoglycosides, tetracyclines, chloramphenicol, and
erythromycin interfere with mechanisms involved in the synthesis of proteins. Quinolones
inhibit bacterial DNA gyrase. Most antivirals work by inhibiting viral replication. In all
cases, the clinical utility is significantly increased when the drug exhibits selectivity for
biochemical processes of the target that are not shared by humans.
   Much of current cancer chemotherapy (antineoplastic agents) involves the use of
substances that are cytotoxic. In general, current antineoplastic drugs can be divided into
four major classes: alkylating agents, antimetabolites, alkaloids, and antibiotics. Alky-
lating agents bind covalently to DNA, thereby impeding replication and transcription,
leading to cell death. Antimetabolite drugs compete with critical precursors of RNA and
DNA synthesis, thereby inhibiting cell proliferation. Alkaloids inhibit microtubular for-
mation and topoisomerase function, thereby blocking cell division and DNA replication.
Certain antibiotics inhibit RNA and DNA synthesis.
   Excess gastric acidity is reduced by treatment with antacids, which are weak bases that
convert gastric (hydrochloric) acid to water and a salt. Most antacids in current use contain
aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, or a calcium salt.
   The mechanisms of action just discussed do not involve overt efforts to communicate
with the normal ongoing physiological processes of the host. The chemical nature of
cellular function and the communication within and between cells allows for modulation
by endogenous chemical substances, drugs or nutrients. The targets of modulation
include enzymes, DNA, and a variety of other molecules involved in the synthesis,
storage, or metabolism of endogenous substances. Efforts to modulate processes that
involve nervous system control directly or indirectly involve interaction with receptors.

3.2. Receptors
    Many drugs interact with macromolecular components of cells that then initiate a
chain of events which leads to the drug’s effect. In a commonly used analogy, the receptor
is like a light switch. A better analogy is that a receptor is like a dimmer switch because
there is generally tonic activation. A receptor also serves to limit access to the switch to
specific molecules (lock and key fit).
   The most widely supported theory holds that receptors are activated when specific
molecules bind (form weak intermolecular chemical bonds) to them and that the magni-
tude of such a drug’s effect is related to the number (or the fraction of the total) receptors
Chapter 2 / Drug Disposition and Response                                                    37

that are occupied (14). The formation of drug–receptor complexes is usually reversible,
such that the reaction between drug molecule (D) and receptor molecule (R) is an equi-
librium reaction that can be described and characterized—as any other equilibrium reac-
tion—according to D + R        DR. The driving force for the reaction to proceed in the
direction of drug–receptor complex depends on the Gibb’s free energy difference ( G)
according to G = –RT ln Keq, where R is the gas constant, T is temperature (Kelvin) and
Keq is the equilibrium constant (15).
   The vast majority of chemical substances cannot just fit a binding site on any receptor.
Chemicals that bind to receptors are said to do so with a certain affinity, the magnitude
of which is given by the reciprocal of the equilibrium constant, 1/Keq (often designated
as Kd). Only a subset of substances that bind to receptors are also capable of eliciting an
effect through the receptor (i.e., have intrinsic activity or efficacy). Substances that have
affinity and intrinsic activity are termed agonists, substances that have affinity, but not
intrinsic activity are termed antagonists. Antagonists competitively or noncompetitively
inhibit the access of agonists to their receptors. In the body, receptors mediate the effects
of endogenous agonists such as neurotransmitters, hormones, peptides, and so on. There-
fore, antagonist drugs—although lacking intrinsic activity—can produce biological
effects by attenuating the signal of the endogenous agonist.
   One of the major functions of receptors is to provide the fidelity of the communication
between neurons or other cells. The lock and key fit restricts access to molecules of
specific three-dimensional shape. The fit is sufficiently flexible, however, that certain
molecules (drugs) having three-dimensional shapes similar to the endogenous ligand can
bind to their receptors (with greater or lesser affinity and intrinsic activity). In such cases,
the fidelity of the normal signal is maintained by the chain of events that occurs post-
receptor occupation (i.e., the signal transduction).
   The number of receptors expressed at any given time is the difference between the
number synthesized and the number destroyed or internalized and, thus, is a function of
the age, health, and other characteristics of the individual. Additionally, repeated expo-
sure to an agonist or antagonist can alter the number of expressed receptors. The change
in receptor number is often interpreted as the body’s attempt to counteract the action of
the agonist or antagonist in an effort to reestablish homeostasis. More permanent change
in receptor number can result from drug effects at the level of the gene.

3.3. Signal Transduction
    Signal transduction refers to the post-receptor electrophysiological or biochemical
sequence of events that lead to an agonist’s effect. Broadly, transduction mechanisms can
be divided into two types: ionotropic, in which activation of the receptor leads directly
to influx of ions (such receptors can actually comprise the ion channel); and metabotropic,
in which activation of the receptor actuates a series of biochemical second messengers
that mediate the response (16).
38                                           Part I / Overview of Drug–Nutrient Interactions

   Located on the membranes of excitable cells, ligand-gated ion channel receptors
(LGICRs) are comprised of segments of transmembrane proteins that form pores of
specific size and shape that allow the passage of certain ions. The LGICR usually displays
selectivity for certain ions (e.g., Na+, K+, Ca2+, or Cl–). The magnitude or the rate of flow
of the ions through the membrane is regulated by the binding of ligand to the LGICR. The
receptor can be composed of subunits that can be expressed or coupled in different ways
in different cells, thus mediating varied effects. Examples of LGICRs are the nicotinic
cholinergic, GABAA, glutamate, glycine receptors.
   The G protein-coupled receptors (GPCRs) often include seven transmembrane (7-
TM) regions, an N-terminal extracellular region, and a C-terminal intracellular region
(17). A group of guanosine triphosphate (GTP) protein subtypes are coupled to the
receptor. Ligand activation of a GPCR induces guanosine 5'-diphosphate (GDP)-GTP
exchange and modulation of associated second messengers such as adenylate cyclase,
phosphoinositide pathways, and ion channels. Multiple G protein subtypes allow for
selective responses (18).
   These receptors span the cell membrane and their self-contained catalytic domain
functions as an enzyme. Examples include receptors for certain growth factors and insulin.
   These intracellular receptors modulate the activity of DNA or other regulatory mol-
ecules located within the nucleus and, consequently, the activation or inhibition of these
receptors influences the synthesis and regulation of proteins (e.g., enzymes and recep-
tors) and other cellular components.

3.4. Dose–Response Curves
   The relationship between a dose and the corresponding response is a useful measure
of drug–nutrient action from both a mechanistic and a practical standpoint. For example,
the most commonly observed shape of a dose–response curve is consonant with the
occupation theory. Given a reaction scheme of the form D + R DR, it follows that the
shape of the dose–response curve should be of the form that is actually observed experi-
mentally (hyperbolic) (19). Additionally, certain features of a dose–response curve—or
a comparison between them—can yield valuable clinically useful information, such as a
measure of relative potency or efficacy.
   Several ways of displaying a dose–response curve are described in the following. The
type of display can affect certain mathematical (statistical) analyses of the data, but this
is beyond the present scope (20).
3.4.1. QUANTAL
   A quantal dose–response curve is one in which the dependent variable (usually plotted
along an ordinate; the y-axis) is measured as an all-or-none outcome (e.g., the number of
patients with systolic blood pressure greater than 140 mmHg). If plotted on rectangular
Chapter 2 / Drug Disposition and Response                                                    39

Fig. 2. (A) A quantal dose–response curve on rectangular coordinates. (B) A graded dose–response
curve on rectangular coordinates.

coordinates, the set of points that are derived from plotting response against the admin-
istered dose (plotted along an abscissa; the x-axis) typically forms a pattern that approxi-
mates a rectangular hyperbola (Fig. 2A).
3.4.2. GRADED
   A graded dose–response curve is one in which the dependent variable (usually plotted
along an ordinate; the y-axis) is measured using a continuous scale (e.g., systolic blood
pressure in mmHg). As with a quantal response, if plotted on rectangular coordinates, the
set of points derived from plotting the measured response against the administered dose
(plotted along an abscissa; the x-axis) typically forms a pattern that approximates a
rectangular hyperbola (Fig. 2B).
3.4.3. LOG
   For practical, and now partly unnecessary but historical reasons, dose–response curves
are commonly constructed by plotting the response against the logarithm (base 10) of the
dose. The shape of such curves becomes sigmoidal or S-shaped (Fig. 3). This has become
so customary that such a plot is often what is meant by a dose–response curve.
   From a dose–response curve it is possible to estimate the dose that would produce a
specified level of effect. The choice of level is arbitrary, but the 50% effect level is
convenient and commonly selected. The dose of drug estimated to produce 50% effect
is termed the ED50 (or equivalent) for a quantal dose–response curve and the D50 (or
equivalent) for a graded dose–response curve. Potency is a comparative term that refers
40                                                Part I / Overview of Drug–Nutrient Interactions

Fig. 3. Quantal or graded dose–response data plotted against log10(dose).

Fig. 4. (A) Potency is indicated by the location of a dose–response curve along the x-axis. (B) Efficacy
is indicated by the maximal-attainable level of effect.
Chapter 2 / Drug Disposition and Response                                                                 41

to the amount of substance required to produce a specified level of effect (Fig. 4A).
Efficacy is a term that refers to a substance’s maximal achievable level of effect (Fig. 4B).
Potency and efficacy are independent characteristics.
    Antagonists, although lacking intrinsic activity, can produce effects when they attenu-
ate the action of an endogenous agonist involved in a pathway that is tonically active and
is in opposition to another pathway. For example, antagonists of the muscarinic cholin-
ergic receptor attenuate the parasympathetic influence on heart rate, with consequent
increase in heart rate owing to the less opposed influence of the sympathetic subdivision.
Hence, such effects of an antagonist can be characterized by dose–response curves.

   The principles of drug disposition and response outlined in this chapter form the basis
for understanding DNIs discussed throughout this volume.

 1. Rang HP, Dale MM, Ritter JM, et al. Pharmacology. Churchill Livingstone, New York, NY, 1995,
    pp. 74–79.
 2. Jacob LS. NMS Pharmacology (4th ed.). Williams & Wilkins, Philadelphia, PA, 1996, pp. 3–4.
 3. Xie H-G, Kim RB, Wood AJJ, et al. Molecular basis of ethnic differences in drug disposition and
    response. Annu Rev Pharmacol Toxicol. 2001;41:815–850.
 4. Pratt WB. The entry, distribution, and elimination of drugs. In: Pratt WB, Taylor P, eds. Principles
    of Drug Action: The Basis of Pharmacology (3rd ed.). Churchill Livingstone, New York, NY, 1990,
    pp. 231–236.
 5. Holford NHG, Benet LZ. Pharmacokinetics and pharmacodynamics: dose selection & the time course
    of drug action. In: Katzung BG, ed. Basic & Clinical Pharmacology (7th ed.). Appleton & Lange,
    Stamford, CT, 1998, pp. 34–49.
 6. de Boer AG, van der Sandt ICJ, Gaillard PJ. The role of drug transporters at the blood-brain barrier. Annu
    Rev Pharmacol Toxicol 2003;43:629–656.
 7. Levine RR. Pharmacology: Drug Actions and Reactions (5th ed.). Parthenon, New York, NY, 1996,
    pp. 51–74.
 8. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: the dynamics of drug absorption, distribution, and
    elimination. In: Hardman JG, Limbird LE, eds. Goodman & Gilman’s the Pharmacological Basis of
    Therapeutics (9th ed.). McGraw-Hill, New York, NY, 1996, pp. 11–16.
 9. Lin JH, Lu AYH. Inhibition and induction of cytochrome P450 and the clinical implications. Clin
    Pharmacokinet 1998;35:361–390.
10. Park BK, Kitteringham NR, Pirmohamed M, et al. Relevance of induction of human drug-metabolizing
    enzymes: pharmacological and toxicological implications. Brit J Clin Pharmacol 1996;41:477–491.
11. Lin JH, Lu AYH. Interindividual variability in inhibition and induction of cytochrome P450 enzymes.
    Annu Rev Pharmacol Toxicol 2001;41:535–567.
12. Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics (3rd ed.). Appleton & Lange,
    Stamford, CT, 1993, pp. 265–292.
13. Raffa RB. Mechanisms of drug action. In: Raffa RB, ed. Quick Look Pharmacology. Fence Creek,
    Madison, CT, 1999, pp. 14–15.
14. Boeynaems JM, Dumont JE. Outlines of Receptor Theory. Elsevier/North-Holland, Amsterdam, 1980.
15. Raffa RB. Drug-Receptor Thermodynamics: Introduction and Applications. Wiley, Chichester,
    UK, 2001.
16. Roerig SC. Drug receptors and signaling. In: Raffa RB, ed. Quick Look Pharmacology. Fence Creek,
    Madison, CT, 1999, pp. 16–17.
42                                                Part I / Overview of Drug–Nutrient Interactions

17. Strader CD, Fong TM, Tota MR, et al. Structure and function of G protein-coupled receptors. Annu Rev
    Biochem 1994;63:101–132.
18. Gudermann T, Kalkbrenner F, Schultz G. Diversity and selectivity of receptor-G protein interaction.
    Annu Rev Pharmacol Toxicol 1996;36:429–459.
19. Tallarida RJ, Jacob LS. The Dose–Response Relation in Pharmacology. Springer-Verlag, New York,
    NY, 1979.
20. Tallarida RJ. Drug Synergism and Dose-Effect Data Analysis. Chapman & Hall/CRC, Boca Raton,
    FL, 2000.
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                                43

      3           Drug-Metabolizing Enzymes
                  and P-Glycoprotein

                  Thomas K. H. Chang

    A drug interaction occurs when a drug or another substance modifies the pharmaco-
kinetics or pharmacodynamics of a concurrently ingested drug. With respect to a phar-
macokinetic drug interaction, the underlying mechanism may be the result of an alteration
in drug absorption, distribution, biotransformation, or excretion. The most common
pharmacokinetic drug interactions are those involving biotransformation, particularly
the ones resulting from induction or inhibition of cytochrome P450(CYP) enzymes (1).
It is now recognized that drug-transport proteins, such as P-glycoprotein (P-gp), play a
critical role in drug disposition (2) and are therefore targets for drug interaction (3).
Various types of drug interactions exist, including drug–drug interaction, nutrient–drug
interaction, food–drug interaction, and herb–drug interaction (4). In some cases, the
consequences of a drug interaction are not clinically significant, but in other instances,
it may lead to therapeutic failure (5), severe adverse events (6), or even fatality (7). In fact,
adverse effects due to drug interactions are one of the leading causes of deaths in hospi-
talized patients (8). Drug interactions also have a high economic cost to the pharmaceu-
tical industry because drugs have been withdrawn from the market as a result of adverse
consequences. In some cases, the effect of a drug interaction may be beneficial because
it reduces the need of a drug (9).
    The purpose of this chapter is to provide an overview of the human CYPs, uridine
diphosphate glucuronosyltransferase (UGT), glutathione S-transferase (GST), and P-gp.
The focus is on the function, induction, inhibition, tissue distribution, and pharmacoge-
netics of these proteins in humans.

  CYP enzymes are a superfamily of hemoproteins involved in the biotransformation of
numerous drugs and other chemicals. Each CYP enzyme is denoted by an Arabic numeral
designating the family (e.g., CYP1 family), a letter indicating the subfamily (e.g., CYP1A

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
44                                            Part I / Overview of Drug–Nutrient Interactions

subfamily), and an Arabic numeral representing the individual gene (e.g., CYP1A2 gene)
(10). CYP enzymes in the same family have greater than 40% amino acid identity and
those in the same subfamily have greater than 55% identity (10). Currently, there are 57
functional human CYP genes (11). CYP enzymes that play a significant role in human
drug metabolism are primarily in the CYP1, CYP2, and CYP3 families. This overview
focuses on CYP3A, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP2E1, which are
the major human CYP drug-metabolizing enzymes.

2.1. CYP3A
   At least two CYP3A proteins are expressed in adult human liver. They are CYP3A4
and CYP3A5 (12). CYP3A4 protein has been detected in all human liver samples and it
represents, on average, approx 30% of the total CYP content in adult human liver (13).
In contrast, the CYP3A5 protein is detectable in only 20% of adult human liver samples
(14). Both CYP3A4 and CYP3A5 have been detected along the gastrointestinal (GI) tract
(15–18). In the case of the CYP3A5 protein, it is also present in the kidney (19,20), lung
(21,22), and pancreas (17).
   More than 30 single nucleotide polymorphisms (SNPs) have been identified just in the
CYP3A4 gene. Among the CYP3A4 allelic variants, CYP3A4*1B (A392 G) is the
most common (23). Its expression varies in different ethnic groups, ranging from 0% in
Chinese and Japanese to 45% in African Americans (24–26). However, this polymor-
phism does not appear to have any functional consequences with respect to drug clear-
ance (24,27,28). To date, 12 allelic variants of CYP3A5 have been identified. The most
common is CYP3A5*3B (A6986 G), which is present in 95% of Caucasians and 27%
of African Americans (29). The homozygote CYP3A5*3B genotype is associated with
very low or undetectable CYP3A5 protein expression (29). The functional consequences
of this genetic variant remain to be determined.
   Numerous drugs with diverse chemical structures and pharmacological functions are
substrates for the CYP3A4 and CYP3A5 enzymes (Table 1), which are usually referred
to as CYP3A because most of the probes are unable to distinguish the function of CYP3A4
from that of CYP3A5. Both the expression and catalytic activity of these enzymes are
subject to modulation (Table 1). CYP3A is inducible not only by drugs, such as rifampin
(30), phenobarbital (31), phenytoin (32), carbamazepine (32), and efavirenz (33), but
also by a herb, St. John’s wort (34–37). It is now known that the mechanism of CYP3A
induction involves transcriptional activation of the gene mediated by receptors, including
the pregnane X receptor (38), which is also known as the steroid and xenobiotic receptor
(39) and the pregnane-activated receptor (40), the constitutive androstane receptor (41),
and the glucocorticoid receptor (42). For example, it has been reported that St. John’s
wort activates the pregnane X receptor and this was mediated by hyperforin, but not by
hypericin (43). In contrast to enzyme induction in which protein expression is enhanced,
CYP3A protein levels can be reduced, as demonstrated by studies with grapefruit juice
and Seville orange juice. In biopsy samples taken from human subjects, the ingestion of
grapefruit juice (44) or Seville orange juice (45) was associated with a decrease in enterocyte
CYP3A protein expression. These effects were attributed to 6',7'-dihydroxybergamottin
(45), which are present in grapefruit juice and Seville orange juice. However, grapefruit
juice, but not Seville orange juice, enhances the bioavailability of cyclosporine (45).
Additionally, the activity of CYP3A enzymes can be altered by the co-administration of
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                        45

      Table 1
      CYP3A Substrates, Inducers, and Inhibitors in Humans
      Substrate (Reference)        Inducer (Reference)        Inhibitor (Reference)
      Alfentanil (213)            Carbamazepine (32)         Amiodarone (214)
      Alprazolam (215)            Efavirenz (33)             Clarithromycin (216)
      Amprenavir (217)            Phenobarbital (31)         Delavirdine (218)
      Amitriptyline (219)         Phenytoin (32)             Diltiazem (220)
      Bosentan (221)              Rifampin (30)              Erythromycin (222)
      Budesonide (223)            St. John’s Wort (35)       Grapefruit Juice (224)
      Buspirone (225)             Troglitazone (226)         Indinavir (227)
      Cyclosporine (228)                                     Itraconazole (229)
      Dextromethorphan (230)                                 Ketoconazole (47)
      Dapsone (231)                                          Methadone (232)
      Docetaxel (233)                                        Nelfinavir (227)
      Ethinylestradiol (234)                                 Nefazodone (235)
      Erythromycin (236)                                     Propofol (237)
      Felodipine (238)                                       Ritonavir (239)
      Indinavir (46)                                         Troleandomycin (240)
      Ifosfamide (241)
      Imipramine (240)
      Irinotecan (242)
      Losartan (243)
      Lovastatin (220)
      Methylprednisolone (244)
      Midazolam (245)
      Nelfinavir (246)
      Nifedipine (247)
      Pimozide (248)
      Quinidine (249)
      Quinine (250)
      Ritonavir (251)
      Ropivacaine (109)
      Saquinavir (205)
      Sildenafil (252)
      Simvastatin (253)
      Tacrolimus (254)
      Triazolam (47)
      Verapamil (255)
      Vincristine (256)

drugs or other substances (e.g., grapefruit juice) that are inhibitors of these enzymes
(Table 1). Clinically significant CYP3A-mediated drug–drug interactions include the
enhanced clearance of indinavir by carbamazepine that may lead to anti-HIV therapeutic
failure (46) and the reduced clearance and excessive pharmacological effect of a benzo-
diazepine hynoptic, triazolam, by ketoconazole or itraconzaole (47).
46                                           Part I / Overview of Drug–Nutrient Interactions

2.2. CYP2C9
   CYP2C9 is a major CYP enzyme expressed in liver and it can account for up to 30%
of the hepatic total CYP content (48). It is primarily a hepatic enzyme, but it has also been
detected in human intestinal microsomes (49). CYP2C9 is important in the in vivo
metabolism of many drugs (Table 2), including tolbutamide (50), S-warfarin (51),
phenytoin (52), losartan (53), celecoxib (54), and glyburide (55).
   Allelic variants of CYP2C9 have been identified (56,57). Compared to individuals with
the CYP2C9*1 allele (i.e., the wild-type), patients with the CYP2C9*2 (Arg144 Cys144)
or the CYP2C9*3 (Ile359 Leu359) allele have a decreased clearance of warfarin and a
reduced daily dose requirement for the drug (51,58,59). However, individuals with these
alleles do not appear to be more likely to experience severe bleeding complications
during long-term therapy (60). The effect of CYP2C9 genetic polymorphism is drug-
specific. For example, there is no relationship between CYP2C9 genotype (i.e.,
CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3, and
CYP2C9*3/*3) and the metabolism of diclofenac in humans (61). Ethnic differences
exist in the frequency distribution of the CYP2C9 allele. The CYP2C9*2 allele is absent
in Chinese subjects, but it is present in up to 10% of Caucasian Americans (57). By
comparison, the CYP2C9*3 allele is expressed in 2–5% of Chinese subjects and up to
20% of Caucasian Americans (57).
   The CYP2C9 enzyme is also subject to induction and inhibition. Rifampin is an
inducer of this enzyme in humans (Table 2), and this drug increases the clearance of
CYP2C9 drug substrates, such as tolbutamide (62), phenytoin (63), and S-warfarin (64).
Inhibitors of this enzyme include fluconazole (65), miconazole (66), fluvastatin (67),
amiodarone (68), sulphamethoxazole (69), and trimethoprim (69). An example of a
clinically significant drug–drug interaction involving CYP2C9 is the inhibition of war-
farin clearance by fluconazole (70).
2.3. CYP2C19
   CYP2C19 is expressed primarily in human liver, although immunoreactive CYP2C19
protein has been detected in human intestinal microsomes (49). CYP2C19 is subject to
genetic polymorphism. To date, eight alleles of CYP2C19 have been identified (71). The
CYP2C19*2, CYP2C19*3, CYP2C19*4, and CYP2C19*6, and CYP2C19*7 alleles are
associated with enzymes that have no functional activity, whereas CYP2C19*5 and
CYP2C19*8 alleles result in enzymes that have reduced catalytic activity (72). Ethnic
differences exist in the frequencies of the CYP2C19 poor metabolizer phenotype, as
assessed by the capacity to metabolize the p-hydroxylation of (S)-mephenytoin. For
example, 12–20% of Asians are poor metabolizers, whereas the frequency is only 2–6%
in Caucasians (73).
   CYP2C19 catalyzes the metabolism of many drugs in humans (Table 3). It is the major
enzyme that metabolizes omeprazole (74), lansoprazole (75), and pantoprazole (76). The
enzyme can be induced by rifampin (Table 3), based on the finding that the administration
of this drug to human subjects increases the urinary excretion of (S)-mephenytoin (77,78).
Another inducer of CYP2C19 is artemisinin. This antimalarial agent decreases the area
under the concentration-time curve (AUC) of omeprazole in human subjects (79). A
number of drugs have been shown to inhibit CYP2C19 in vivo (Table 3), including
omeprazole (80), ticlopidine (81), ketoconazole (82), fluoxetine (83), fluvoxamine (83),
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                           47

         Table 2
         CYP2C9 Substrates, Inducers, and Inhibitors in Humans
         Substrate (Reference)    Inducer (Reference)   Inhibitor (Reference)
         Celecoxib (54)             Rifampin (62)       Amiodarone (68)
         Glyburide (55)                                 Fluconazole (65)
         Phenytoin (52)                                 Fluvastatin (67)
         Tolbutamide (50)                               Miconazole (66)
         S-Warfarin (51)                                Sulphamethoxazole (69)
                                                        Trimethoprim (69)

     Table 3
     CYP2C19 Substrates, Inducers, and Inhibitors in Humans
     Substrate (Reference)       Inducer (Reference)     Inhibitor (Reference)
     Amitriptyline (257)           Artemisinin (79)         Cimetidine (87)
     Citalopram (258)              Rifampin (77)            Fluoxetine (83)
     Clomipramine (259)                                     Fluvoxamine (83)
     Diazepam (260)                                         Isoniazid (84)
     Fluoxetine (261)                                       Ketoconazole (82)
     Imipramine (262)                                       Moclobemide (85)
     Lansoprazole (75)                                      Omeprazole (80)
     Moclobemide (85)                                       Oral contraceptives (86)
     Nelfinavir (263)                                       Ticlopidine (81)
     Omeprazole (74)
     Pantoprazole (54)
     Phenytoin (264)
     Proguanil (265)
     Propranolol (266)
     Sertraline (267)

isoniazid (84), moclobemide (85), and oral contraceptives (86). Inhibition of CYP2C19
occurs in a gene-dose dependent manner such that the extent of inhibition is the greatest
in homozygous extensive metabolizers, intermediate in heterozygous extensive
metabolizers, and little or no inhibition in homozygous poor metabolizers (72). Clinically
relevant drug–drug interactions involving CYP2C19 include the inhibition of phenytoin
metabolism by fluoxetine (87), cimetidine (87), isoniazid (84), and felbamate (87),
resulting in increased phenytoin toxicity.
2.4. CYP2D6
   CYP2D6 is expressed in human liver, but at a level (2–5% of total CYP content) less
than that of CYP3A, CYP2C9, and CYP1A2. This protein is also present in various
extrahepatic tissues, including the GI tract (88), brain (89,90), and lung (91), but at much
lower levels when compared to the liver.
   An important aspect of CYP2D6 is that many allelic variants (>50) of this enzyme have
been identified, although most are quite rare. CYP2D6*1 is the wild-type, whereas
CYP2D6*9, CYP2D6*10, and CYP2D6*17 have reduced activity (intermediate
48                                          Part I / Overview of Drug–Nutrient Interactions

metabolizer phenotype), and others such as CYP2D6*3, CYP2D6*4, CYP2D6*5,
CYP2D6*6 have no functional activity (poor metabolizer phenotype) (92). In some
individuals, genetic duplication of the CYP2D6*2 allele results in enhanced functional
capacity and this leads to the ultra-rapid metabolizer phenotype (93). Ethnic differences
also exist in the frequency in which the various CYP2D6 alleles are expressed. A striking
example is with CYP2D6*10, which is expressed in up to 70% of Chinese subjects, but
only in 5% of Caucasians (94). In contrast, CYP2D6*4 is present in approx 20% of
Caucasians (95), but in less than 1% of Japanese subjects (96). For drugs such as codeine,
hydrocodone, and oxycodone, the consequences of a poor metabolizer phenotype is
particularly significant because these drugs are bioactivated by CYP2D6. In fact, it has
been suggested that codeine not be prescribed to patients with a CYP2D6 poor metabolizer
phenotype (97).
   Numerous clinically useful drugs are substrates for CYP2D6 (Table 4), including
many of the analgesics, antiarrhythmics, -blockers, antidepressants, antipsychotics, and
antiemetics. Various drugs can inhibit the functional activity of CYP2D6 (Table 4).
Quinidine is a potent and enzyme-specific inhibitor of CYP2D6. There is no conclusive
evidence that CYP2D6 is subject to enzyme induction by drugs. However, CYP2D6-
mediated drug clearance appears to be enhanced during pregnancy (98–100). An example
of a CYP2D6-mediated drug–drug interaction is the inhibition of venlafaxine clearance by
diphenhydramine (101).

2.5. CYP1A2
   CYP1A2 is expressed primarily in liver, with little or no known extrahepatic expres-
sion (102). This enzyme is important in the bioactivation of aromatic amines and hetero-
cyclic amines (103) and metabolism of clinically useful drugs (Table 5), including caffeine
(104), clozapine (105,106), melatonin (107), mexiletine (108), ropivacaine (109), tacrine
(110), theophylline (111), and verapamil (112). Large interindividual differences (up to
100-fold) in human hepatic CYP1A2 protein content have been reported (113–115),
which may be the result of genetic or environmental factors. Allelic variants of CYP1A2
have been identified in recent years. The G2964A and C734A polymorphisms are asso-
ciated with high CYP1A2 inducibility (116,117), whereas the A164C and T2464delT
polymorphisms have no effect on CYP1A2 phenotype, as determined by the caffeine
metabolic ratio (118). This enzyme is subject to induction by various factors (Table 5),
including exposure to environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-
p-dioxin (119), cigarette smoking (120), consumption of charbroiled meats (121) and
cruciferous vegetables (122,123), and ingestion of drugs (i.e., carbamazepine [124]).
The catalytic activity of CYP1A2 can be inhibited by drugs (Table 5), such as
ciprofloxacin (125), enoxacin (126), fluvoxamine (83), oltipraz (127), and stiripentol
(128). CYP1A2-mediated drug–drug interactions have been reported; for example, the
inductive effect of cigarette smoking (120) and the inhibitory effect of ciprofloxacin
(125) on drugs metabolized extensively by CYP1A2.

2.6. CYP2E1
   CYP2E1 is expressed in adult (13,129) and fetal liver (130), in addition to lung (131),
placenta (131), and brain (132). Whereas a large number of small molecular weight
organic solvents (e.g., ethanol) are substrates for CYP2E1, only a few drugs have been
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                       49

                Table 4
                CYP2D6 Substrates and Inhibitors in Humans
                 Substrate (Reference)        Inhibitor (Reference)
                Amitriptyline (257)              Amiodarone (268)
                Carvedilol (269)                 Cimetidine (270)
                Chlorpheniramine (271)           Citalopram (83)
                Cilostazol (272)                 Diphenhydramine (273)
                Citalopram (258)                 Fluoxetine (83)
                Clomipramine (259)               Fluvoxamine (83)
                Codeine (274)                    Methadone (275)
                Desipramine (276)                Moclobemide (85)
                Dextromethorphan (277)           Paroxetine (83)
                Dihydrocodone (278)              Propafenone (279)
                Encainide (280)                  Quinidine (281)
                Flecainide (282)                 Sertraline (283)
                Fluoxetine (284)                 Terbinafine (285)
                Fluvoxamine (286)
                Haloperidol (287)
                Hydrocodone (288)
                Imipramine (289)
                Methylphenidate (290)
                Metoprolol (291)
                Mexiletine (292)
                Nefazodone (293)
                Nicergoline (294)
                Nortriptyline (295)
                Ondansetron (296)
                Oxycodone (297)
                Perphenazine (298)
                Procainamide (299)
                Propafenone (300)
                Propranolol (266)
                Risperidone (301)
                Tramadol (302)
                Tropisetron (303)
                Venlafaxine (304)
                Zuclopenthixol (298)

found to be metabolized by CYP2E1 (Table 6); that is, acetaminophen (133),
chlorzoxazone (134), enflurane (135), and sevoflurane (136). Several SNPs of the human
CYP2E1 gene have been identified, but they are not functionally relevant (137). Various
factors can influence the activity of this enzyme (Table 6). Chronic alcohol consumption
is associated with an increase in hepatic CYP2E1-mediated enzyme activity (138,139)
and this is accompanied by elevated protein and mRNA expression (140). The levels of
this enzyme are also elevated by fasting (141), in individuals with obesity (141,142) or
diabetes (143,144), and in patients with nonalcoholic steatohepatitis (145). This enzyme
can also be induced by isoniazid (138,146) and all-trans-retinoic acid (147). Inhibitors
50                                            Part I / Overview of Drug–Nutrient Interactions

      Table 5
      CYP1A2 Substrates, Inducers, and Inhibitors in Humans
       Substrate (Reference)       Inducer (Reference)             Inhibitor (Reference)
      Caffeine (104)            Charcoal-broiled meat (121)      Ciprofloxacin (125)
      Clozapine (105)           Cigarette smoke (305)            Enoxacin (126)
      Melatonin (107)           Cruciferous vegetables (123)     Fluvoxamine (83)
      Mexiletine (108)          Carbamazepine (124)              Oltipraz (127)
      Ropivacaine (109)                                          Stiripentol (128)
      Tacrine (110)
      Theophylline (111)
      Verapamil (112)

Table 6
CYP2E1 Substrates, Inducers, and Inhibitors in Humans
 Substrate (Reference)         Inducer (Reference)                 Inhibitor (Reference)
Acetaminophen (133)      Alcohol, multiple doses (138)         Alcohol, single dose (148)
Chlorzoxazone (134)      All-trans-retinoic acid (147)         Black tea (152)
Dapsone (306)            Diabetes (144)                        Broccoli (152)
Enflurane (135)          Fasting (141)                         Chlormethiazole (150)
Sevoflurane (136)        Isoniazid (multiple doses) (146)      Diallyl sulfide (148)
                         Nonalcoholic steatohepatitis (145)    Disulfiram (149)
                         Obesity (142)                         Isoniazid (single dose) (146)
                                                               Watercress (151)

of CYP2E1 are ethanol (acute ingestion) (148), disulfiram (149), chlormethiazole (150),
diallyl sulfide (148), watercress (151), broccoli (152), and black tea (152). A clinically
significant CYP2E1-mediated drug interaction is the inhibition of acetaminophen
bioactivation by acute intake of alcohol (153). Interestingly, this metabolic reaction is
enhanced by the consumption of multiple alcoholic drinks prior to ingestion of acetami-
nophen (154).

   In contrast to CYP, considerably less is known about the regulation and function of
other drug-metabolizing enzymes, such as the UGT and the GST enzymes (see Subhead-
ing 4.). The UGTs are a superfamily of enzymes that catalyze the conjugation of drugs
and other compounds, with UDP-glucuronic acid as a cosubstrate. In general, this type
of metabolic reaction results in more polar and less toxic metabolites. Each UGT enzyme
is denoted by an Arabic number designating the family (e.g., UGT1 family), a letter
indicating the subfamily (e.g., UGT1A subfamily), and an Arabic number denoting the
individual gene (e.g., UGT1A1 gene) (155). UGT enzymes in the same family have
greater than 45% amino acid identity and those in the same subfamily have greater than
60% identity (155). In humans, two families of UGT enzymes have been identified to
date, UGT1 and UGT2 (156). The individual enzymes are UGT1A1, UG1A3, UGT1A4,
UGT1A6, UGT1A7, UG1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B10,
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                           51

UGT2B11, UGT2B15, and UGT2B17 (157,158). The mRNA of these enzymes is
expressed in human liver, except for UGT1A7, UGT1A8, and UGT1A10 (158). Extra-
hepatic expression has been reported (156,159,160), including small intestine
(UGT1A1, UGT1A3, UGT1A4, UGT1A8, UGT1A10, UGT2B15), colon (UGT1A1,
UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT1A10), stomach (UGT1A6, UGT1A7,
and UGT1A10), kidney (UGT1A9 and UGT2B7), prostate (UGT2B15 and UGT2B17),
and brain (UGT1A6 and UGT2B7).
   Polymorphisms in the UGT1A1, UGT1A6, UGT2B4, UGT2B7, and UGT2B15 genes
have been discovered (161). Mutation in the UGT1A1 gene, as the consequence of having
a thymine-adenine (TA)-repeat greater than six, leads ultimately to the absence of the
UGT1A1 enzyme (162). This results in hyperbilirubinemias, such as the Crigler-Najjar
syndrome (163) and Gilbert’s syndrome (162). However, the clinical significance of
UGT genetic polymorphisms on the pharmacokinetics and pharmacodynamics of thera-
peutic agents remains to be established.
   Information on the identity of the specific drug substrates catalyzed in humans by
individual UGT enzymes is lacking. This is because of the absence of suitable UGT
enzyme-selective probes (i.e., inhibitors and inducers) for use in vivo. However, pharma-
cokinetic studies have shown that many clinically useful drugs undergo glucuronidation in
humans. Drugs that are glucuronidated at substantial levels ( 50% of the administered
dose) include chloramphenicol (164), ketoprofen (165), lamotrigine (166), lorazepam
(167), morphine (168), S-naproxen (165), oxazepam (169), propofol (170), temazepam
(171), zidovudine (172), and zomepirac (173).
   UGT enzymes are subject to induction and inhibition in humans. Drugs, such as
rifampin (174), phenobarbital (175), phenytoin (175), carbamazepine (176), and oral
contraceptives (177), have been reported to enhance the glucuronidation of various drugs.
Interestingly, the consumption of watercress, which is a rich source of phenethyl-
isothiocyanate, results in increased glucuronidation of cotinine in smokers (178). Hepatic
UGT enzymes are also induced in smokers (179). Inhibitors of drug glucuronidation
include valproic acid (180), salicylic acid (181), and probenecid (182). With respect to
the inhibition of lamotrigine elimination by valproic acid (183), this drug interaction may
lead to the development of Stevens-Johnson syndrome (184).

   GST enzymes catalyze the glutathione conjugation of electrophilic compounds of
exogenous and endogenous origin. For many chemicals, including drugs, this represents
an important detoxification pathway. In the human cytosolic GST superfamily, there are
at least 16 genes and they are subdivided into eight subclasses (GSTA, GSTK, GSTM,
GSTP, GSTS, GSTT, GSTZ, and GSTO) (185). Additionally, microsomal GST enzymes
have been isolated, but they are structurally distinct from the cytosolic forms. Human
GST enzymes are expressed in a tissue-dependent manner (186–189). For example,
GSTA1 is present at high levels in liver, kidney, and testis, but absent in lung, heart, and
spleen, whereas GSTP1 is expressed in lung, heart, small intestine, and prostate, but
undetectable in liver. Most of the studies on the function of GST enzymes have focused
on the role of these enzymes in the biotransformation of environmental carcinogens.
Much less is known about the specific drugs that are metabolized by GST enzymes.
However, drugs that are known to be in vivo substrates for human GST enzymes include
52                                            Part I / Overview of Drug–Nutrient Interactions

acetaminophen (190), valproic acid (191), and busulfan (192). In humans, polymor-
phisms in the GST genes have been identified (193), but very little is known about the
clinical significance of the GST polymorphisms with respect to the pharmacokinetics and
pharmacodynamics of therapeutic agents. A recent study indicated a lack of a relationship
between the various GSTA1 alleles and the glutathione conjugation of busulfan (194).
Human studies on the induction of GST enzymes are limited. The oral administration of
oltipraz, which has been evaluated as a cancer chemopreventive agent, has been shown
to increase lymphocyte GST enzyme levels in human volunteers (195). In other human
studies, the consumption of Brussels sprouts for 1–3 wk has led to a modest increase in
plasma GSTA levels (196–198). Very little is known about the inhibition of GST enzymes
in humans. In a recent study, the ingestion (daily for 4 mo) of Curcuma extract, which
contains the dietary polyphenol curcumin, was reported to reduce GST activity in lympho-
cytes in human volunteers (199). Similarly, eugenol, which is the main constituent of oil
of cloves, has been shown to reduce human plasma GSTA enzyme activity (200). Overall,
much remains to be investigated about the effect of drugs and other factors on the expres-
sion and catalytic activity of individual GST enzymes in humans.

    It has only been appreciated in the last several years that drug interactions occur not
only as a result of induction or inhibition of drug-metabolizing enzymes, but also drug-
transport proteins, such as P-gp (3). This adenosine 5'-triphosphate-binding cassette
transporter was originally discovered in tumor cells, whereby repeated exposure of the
cells to cytotoxic agents led to overexpression of P-gp (201). Because this membrane-
bound protein functions as an efflux pump, the overexpression of P-gp leads to a reduc-
tion in intracellular drug accumulation, a decrease in cancer chemotherapeutic drug
efficacy, and the development of drug resistance. P-gp is expressed not only in tumor
cells, but also in normal cells, such as epithelial cells on the luminal surface of many
organs, including the liver, intestines, and kidney (202). The general function of P-gp in
the small intestine, liver, and kidney is the secretion of drugs and other chemicals into the
gut lumen, bile, and tubule lumen, respectively. It is also present in the blood–brain
barrier, blood–testis barrier, and placenta to protect the central nervous system, testis, and
fetus from xenobiotics.
    In vitro studies have shown that numerous drugs with diverse chemical structures and
pharmacological function have been reported to be substrates and modulators of P-gp.
Table 7 lists substrates, inducers, and inhibitors of P-gp in humans. An interesting finding
is that some of the substrates, inducers, and, inhibitors of P-gp (e.g., rifampin, St. John’s
wort, clarithromycin, cyclosporine, erythromycin, docetaxel, itraconazole, nelfinavir,
quinidine, and verapamil) are also substrates, inducers, and inhibitors of CYP3A. A
difficulty of this overlapping specificity is that it is difficult to predict the underlying
mechanism of drug interaction. For example, the coadministration of garlic supplements
and saquinavir has been reported to decrease the area under the plasma saquinavir AUC
by 50% (203). However, saquinavir is a substrate for both P-gp (204) and CYP3A (205).
Therefore, it is possible that constituent(s) in garlic is capable of inducing P-gp, CYP3A,
or both of these proteins. In the case of talinolol, this drug is not metabolized by CYP3A,
but is transported by P-gp. Thus, this drug could be utilized as an experimental probe to
Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                         53

       Table 7
       P-glycoprotein Substrates, Inducers, and Inhibitors in Humans
       Substrate (Reference)      Inducer (Reference)       Inhibitor (Reference)
       Cyclosporine (307)         Levothyroxine (207)      Clarithromycin (308)
       Daunorubicin (309)         Rifampin (206)           Cyclosporine (310)
       Digoxin (311)              St. John’s wort (35)     Erythromycin (312)
       Docetaxel (313)                                     Itraconazole (238)
       Doxorubicin (310)                                   Nelfinavir (314)
       Epirubicin (315)                                    Progesterone (316)
       Etoposide (317)                                     Quinidine (318)
       Loperamide (319)                                    Talinolol (320)
       Paclitaxel (321)                                    Valspodar (322)
       Quinidine (229)                                     R-Verapamil (323)
       Saquinavir (204)
       Tacrolimus (324)
       Talinolol (325)
       Teniposide (326)
       Vinblastine (327)

distinguish the effects of CYP3A from those of P-gp. Intestinal P-gp can be induced, as
demonstrated by recent studies with human duodenal biopsy samples showing that
repeated ingestion of rifampin (206), levothyroxine (207), and St. John’s wort (35)
increase duodenal expression of P-gp. Given that rifampin and St. John’s wort induce
both P-gp and CYP3A, drug interactions involving these drugs may be particularly
significant. In fact, the reduction in blood levels of cyclosporine by St. John’s wort (5)
has led to transplant rejection (208).
   More than 20 SNPs in the MDR1 (ABCB1) gene, which encodes P-gp, have been
identified to date (209). Studies have focused primarily on the C3435 T allelic variant,
which occurs at a greater frequency in Caucasians and Asians (40–60%) than in Africans
(<10%) (209). However, the clinical significance of this polymorphism with respect to
pharmacokinetics and pharmacodynamics is not known at the present time. For example,
conflicting data exist on the effect of the C3435 T allelic variant on the disposition of
digoxin (210,211). Furthermore, it does not appear to have any effect on the pharmaco-
kinetics of cyclosporine (28). In a recent report, it was shown that in HIV patients with
the homozygote TT genotype at position 3435 had reduced levels of MDR1 mRNA and
P-gp in peripheral-blood mononuclear cells and a greater increase in CD4-cell count
when determined 6 mo after antiretroviral drug therapy (212). Further studies are
required to confirm these initial findings.

  This overview of enzymes and other proteins involved in human drug disposition
provides a setting in which to appreciate the various drug–nutrient interactions.
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66                                                  Part I / Overview of Drug–Nutrient Interactions

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Chapter 3 / Drug-Metabolizing Enzymes and P-gp                                                             67

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Chapter 4 / Nutrient Disposition and Response                                             69

      4          Nutrient Disposition and Response

                 Francis E. Rosato, Jr.

   Many factors are involved in the development of drug–nutrient interactions (DNIs).
In order to better understand the potential for DNIs, an appreciation for control over food
intake, as well as the digestion, absorption, and elimination of nutrients and their sites of
storage and effect is necessary.

   A variety of factors, including gastrointestinal (GI) physiology, metabolic demands,
external environment, appearance of food, psychological states, social traits, and dis-
ease states have been shown to play important roles in the ongoing cycle of initiating,
maintaining, and terminating food intake (1). However, our understanding of the exact
mechanism of what controls food intake is continually evolving. For years, a specific
anatomic region of the brain was thought to be the only area involved (2). Experiments
with rats were able to identify two regions of the hypothalamus that affected appetite.
Stimulation of the lateral hypothalamus elicited a feeling of hunger while ventromedial
stimulation elicited a feeling of satiety. Since these classic studies, the understanding of
appetite regulation has evolved from an explanation based on anatomic distribution into
one of a complex interaction between the central nervous system (CNS) and the periph-
ery. This includes both short-term control over food intake and long-term control of
energy balance (3).
   Hunger is the feeling that motivates people to seek food. This driving force appears to
be generated by a variety of neuroregulators originating in and acting on specific sites of
the brain. Some of these chemical messengers have been well studied (neuropeptide Y,
opioids, galanin, norepinephrine, and benzodiazepines) (1). These messengers appear to
be under the influence of a multitude of controls that take into account the body’s overall
energy balance, timing of the last meal, taste, smell, appearance of food, emotions,
stressors, gastric volume, exercise, and climate. The end result is food consumption.
   As one continues to eat, hunger is replaced by the feeling of satiety. The stimulus
required to generate this feeling also comes from multiple sources. These inputs are
processed mainly by the brainstem in an area called the nucleus tractus solitarius. This
area receives inhibitory stimuli from the mouth, stomach, and liver via the vagus nerve.

                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
70                                            Part I / Overview of Drug–Nutrient Interactions

Also acting on the brain as appetite suppressants are neuroendocrine secretions from the
periphery like cholecystokinin (CCK) from the small bowel and leptin from adipocytes (2).
Leptin has come to the forefront as a major factor in controlling food intake. This hormone
is produced by adipocytes and has the effect of maintaining satiety. For this reason, it has
been targeted as a possible drug treatment for obesity. Once achieved, the feeling of
satiety leads to the cessation of a meal.
   As time passes, the feeling of satiety waxes and is once again replaced by hunger. And
once again the cycle starts over. Note as well that any number of medications may
interfere at certain signaling points.

3.1. Overview
   Digestion is the mechanical and chemical breakdown of foodstuff to a form that can
be utilized by the body. This process occurs in the GI tract. The GI tract is a tubelike
structure that consists of the mouth, esophagus, stomach, small intestine, large intestine,
and anus. Although its main function is the digestion and absorption of nutrients (macro-
nutrients—carbohydrates, protein, lipid, water; and micronutrients—vitamins, miner-
als), the GI tract also plays a role in the excretion of waste, and maintaining host immune
defenses. There are a number of accessory organs that aid the GI tract in carrying out its
primary task; these include the salivary glands, the liver, the gallbladder, and the pan-
creas. A variety of specialized digestive cells have evolved to meet the requirements of
digestion and include chief cells of the stomach, pancreatic exocrine cells, and brush
border cells of the small intestine. The GI tract orchestrates the use of these accessory
organs and specialized cells in concert to convert carbohydrates, proteins, and fats from
their complex molecular form into their more usable forms of monosaccharides, amino
acids, and free fatty acids. The movement of the digested nutrients from the intestinal
lumen into the blood or lymph fluid is called absorption. Absorption is a highly developed
process that is very site specific and utilizes a variety of transport systems (i.e., passive,
active, and simple diffusion or endocytosis).

3.2. Mouth and Esophagus
   Digestion begins in the mouth where mastication decreases the size of the food bolus
in preparation for its passage down the esophagus. The sight, smell, and taste of food all
lead to the release of saliva and in particular -amylase from the salivary gland. This
enzyme begins the breakdown of dietary starch and remains active until neutralized by
the acidic environment of the stomach. Saliva also serves as an antimicrobial and lubri-
cant to aid in speech and swallowing. Swallowing is a highly coordinated action involv-
ing both voluntary and involuntary muscles. The process culminates in the relaxation of
the lower esophageal sphincter allowing the deposition of a food bolus into the stomach.
Altered physiology of the lower esophageal sphincter muscle leads to the clinical ailment
known as acid reflux.

3.3. Stomach
  The stomach’s main function serves as a reservoir to ready food for absorption by the
small intestine and thus plays a minimal role in the absorption of nutrients. Ethanol and
Chapter 4 / Nutrient Disposition and Response                                                71

short-chain fatty acids (SCFAs) are the only products absorbed by the stomach during a
meal. The lining of the stomach consists of three types of mucosal glands—cardiac,
oxyntic, and antral. These glands contain highly specialized cells as well as simple
mucosal cells. The gland with the most distinctive feature is the oxyntic. This gland
contains both parietal and chief cells. Parietal cells secrete hydrochloric acid (HCl) and
are responsible for maintaining the acid environment of the stomach as well as secreting
intrinsic factor. This latter polypeptide plays an important role in the absorption of vita-
min B12. Chief cells release pepsinogen that is responsible for the digestion of proteins.
The G-cells of the antrum secrete the hormone gastrin important for acid production.
Mucosal cells throughout the stomach secrete mucus and bicarbonate. All of these gastric
cells are under tight neurohormonal regulation. The combination of gastric distention and
nutrients in the stomach leads to an increased release of acetylcholine, histamine, and
gastrin that stimulate the release of HCl and pepsinogen. Pepsinogen is cleaved to its
active form pepsin by HCl. The end result is the onset of chemical breakdown of
nutrients into smaller molecules. To further maximize digestion, the stomach mixes
food particles and gastric juices by continually contracting against the pylorus. This process
of mixing and grinding is called trituration. The gastric phase of digestion is crucial in the
overall absorption of nutrients as proven by a variety of malabsorption syndromes caused
by alterations in gastric physiology or anatomy.
   When a food bolus reaches the stomach, vagal stimulation and gastrin secretion pro-
mote gastric motility (4). So as not to exceed the absorptive capacity of the duodenum,
the body has developed some mechanisms based on food consistency and composition
to regulate gastric emptying (5). Normally, food must be broken down to less than 1–2
mm before it may pass through the pylorus. Thus, food that is poorly chewed or is high
in fiber or fat will take longer to exit the stomach than proteins, which in turn will take
longer to empty than liquids. Another mechanism is the inhibition of gastric motility by
the hormone CCK. This hormone is released in response to high levels of fat and protein
in the lumen of the duodenum. The last mechanism that slows gastric emptying is a
phenomenon known as the “ileal brake.” When incompletely digested carbohydrates are
presented to the terminal ileum, a response to slow down gastric emptying occurs. The
hormone peptide YY is suspected to play a role in this response (4).
3.4. Small Intestine
   The small intestine, which consists of the duodenum, jejunum, and ileum, has several
unique features that allow it to play a significant role in digestion and absorption. First,
the small bowel has the largest surface area of the entire GI tract thanks in part to its length
(about 3 m) and unique anatomic configuration. The entire luminal surface consists of
mucosal folds, each with fingerlike projections called villi. On the surface of each villi
are more fingerlike projections called microvilli. The result is a surface area of approx
200 m2 (5). The small bowel also has a unique mechanism of motility. Contents are
moved in a back and forth motion called segmentation. This ensures adequate mixing of
luminal contents as well as a thorough interaction with the surface area. The cells that line
the intestinal lumen, called enterocytes, are highly specialized. They play roles in digestion,
absorption, storage, and electrolyte balance. Enterocytes are continually being renewed
approximately every 3 d.
   Digestion in the small bowel occurs in two phases—luminal and cellular. The luminal
phase involves the help of the liver, gallbladder, and pancreas. As the acidic chyme is
72                                           Part I / Overview of Drug–Nutrient Interactions

expelled from the stomach the pancreas secretes a bicarbonate rich fluid that acts to raise
the pH in the duodenum. The neutral environment optimizes the activity of pancreatic
digestive enzymes. An enzyme/zymogen-rich cocktail containing amylase, lipase, phos-
pholipase A2, nucleolytic enzymes, trypsinogen, chymotrypsinogen, proelastase,
procarboxypeptidases, and procolipase are excreted by the pancreas in response to the
variety of partially digested nutrients in the duodenum. The benefit of storing enzymes
as inactive zymogens serves to protect the pancreas against autodigestion. Bile salts are
also released from the liver and gallbladder in response to lipids. Bile is a detergent that
acts to compartmentalize small lipid particles into easily absorbable units called micelles.
Also playing roles in the luminal phase are a series of enzymes located on the brush border
of the enterocytes. These enzymes, called ectoenzymes, serve to complete the digestive
process. The end result of the luminal phase is the conversion of most carbohydrates to
monosaccharides, proteins to amino acids and small peptide fragments, and lipids to free
fatty acids and monoglycerides.
   The cellular phase of digestion occurs after nutrients have entered the enterocyte’s
cytoplasm. Once inside the cell, peptidases breakdown di- and tripeptides into free amino
acids. Also present in the enterocyte are enzymes that convert monoglycerides and free
fatty acids back into triglycerides for incorporation into chylomicrons.

3.5. Large Intestine
   The colon plays a limited role in the digestion of nutrients. Nonabsorbed carbohy-
drates that reach the ascending colon are either actively absorbed or converted to SCFAs
by colonic bacteria. This process of fermentation helps to provide a fuel source for
colonocytes. Dietary long-chain fatty acids are broken down but not absorbed. However,
their presence affects water absorption and electrolyte balance. In cases where there is
limited small bowel, the colon has been shown to adapt in order to carry out the absorption
of nutrients.

3.6. Regulation
   The process of digestion falls under the regulation of the CNS, GI hormones, neu-
rotransmitters, and paracrine substances (6). The neuronal axis responds to both external
(smell, appearance) and internal (volume, nutrient content) cues from a meal. Input
carried from cranial, vagal, and visceral afferent neurons stimulate the CNS via acetylcho-
line to increase glandular secretions, gastric motility, and pancreatic exocrine function.
   G-cells of the gastric antrum release the hormone gastrin increasing acid production
and gastric motility. Secretin is released in response to a pH less than 4.5 by S-cells of
the duodenum and jejunum. It stimulates the secretion of bicarbonate by the exocrine
pancreas to neutralize gastric chyme and promotes the release of bile from the liver.
Cholecystokinin is released by I-cells of the duodenum and jejunum in response to fat or
protein in the small bowel. Its action results in the contraction of the gallbladder and the
release of pancreatic digestive enzymes. Somatostatin is a paracrine peptide released by
D-cells of the GI tract and pancreas to reduce overall intestinal secretions, including HCl,
pancreatic juice, and blood flow to the GI tract. A variety of other factors including,
epidermal growth factor, motilin, gastric inhibitory peptide, peptide YY, glucagon-like
peptides, bombesin, and pancreatic peptide play smaller roles in helping to regulate GI
function (7).
Chapter 4 / Nutrient Disposition and Response                                             73

   Absorption is the movement of nutrients, including water and electrolytes, from the
intestinal lumen to the vascular or lymphatic systems. The body has developed several
different types of transport mechanisms to facilitate absorption. These mechanisms can
involve energy dependent or independent pathways, passive or active transport, simple
diffusion, endocytosis, or even paracellular movement. Although the entire small bowel
has the capacity for absorption, the vast majority of nutrients are absorbed by the jejunum.
By the time gastric contents have reached the ileum, the process of nutrient absorption
is near total completion. The best way to understand absorption is to follow the fate of
the individual nutrients as they have been digested.

   The majority of dietary carbohydrates from a healthy diet are derived from plant
starch. Glycogen from meats and disaccharides from refined sugars contribute a much
smaller amount. The end result of digestion is the breakdown of complex (starch and
fibers) and simple carbohydrates (sugars) into the monosaccharides glucose, fructose,
and galactose. These three molecules, all hexoses, share a similar molecular formula. The
major enzymes responsible for the digestion of carbohydrates are salivary amylase,
pancreatic amylase, and brush border disaccharidases. These enzymes cleave the O-OH
bonds between polysaccharides by a process called hydrolysis. After a meal, all carbo-
hydrates are absorbed and only a small portion of resistant starch and dietary fiber remain
undigested. These residual products are fermented to SCFAs by bacteria in the colon,
which are later used as energy.
   For the most part, the absorption of monosaccharides occurs in the small intestine
exclusively through a group of hexose transporters. Glucose and galactose traverse the
apical membrane of enterocytes through a sodium-dependent active transport system
called SGLT-1. Fructose enters the epithelial cells, via facilitated diffusion, through a
separate transport system called GLUT-5. Once inside the epithelial cell, all three
monosaccharides are transported across the basolateral membrane by a passive diffusion
transporter called GLUT-2. Once across the basolateral membrane the hexoses are trans-
ported by the portal system to the liver where their ultimate fate will be determined.
   Glucose can be utilized in three different ways by the body. First, it can be taken up
by the cells of the body with the help of insulin and used to meet immediate energy
demands via glycolysis. The second possibility is that it can be converted to glycogen and
stored for later use. The liver contains one-third of the body’s total glycogen stores and
muscle contains the remaining two-thirds. During periods of low blood glucose the liver
converts glycogen back to glucose to be used to maintain the energy requirements of the
body. Glycogen reserves in muscle are used solely to maintain their own energy require-
ments. The last option for glucose is its conversion to fatty acids for energy or storage as
triglycerides in adipose tissue. This occurs only when the body’s energy needs have been
satisfied and glycogen stores filled.
   A recent field of nutritional study focuses on the interaction of nutrients with genes and
their protein products. Carbohydrates have been shown to effect the production of a
variety of proteins. For example, the presence of glucose, galactose, and fructose in the GI
tract have been shown to cause an increased expression of their respective hexose transport-
ers (7). Also, increased levels of glucose in blood have been shown to up-regulate the
74                                           Part I / Overview of Drug–Nutrient Interactions

production of a myriad of enzymes involved in glycolysis, fructose metabolism, and
gluconeogenesis (7). As we gain a better understanding of this field it is possible that
nutrient–gene interactions could be used for the identification and treatment of a variety
of diseases.
   As one begins to understand the physiology of digestion and absorption it becomes
apparent how malabsorption of carbohydrates can result from a variety of diseases. For
example, pancreatic insufficiency brought on by chronic pancreatitis, surgical resection,
or congenital defect like cystic fibrosis can lead to insufficient amounts of amylase.
Alterations in the function of enterocytes via radiation injury or celiac disease can also
effect carbohydrate absorption. And finally, a decrease in bowel surface area caused by
congenital short gut, inflammatory bowel disease, or surgical resection can result in
inadequate interaction between mucosal cells and nutrients.

    Digestion breaks down proteins into individual amino acids the body can use as it sees
fit. In the stomach, hydrochloric acid denatures proteins exposing their peptide bonds to
the proteolytic enzyme pepsin, breaking down proteins into amino acids and smaller
peptide molecules. This digestive process is accelerated in the small intestine by a variety
of pancreatic proteases. Enterocytes contain an enzyme on their apical border
(enteropeptidase) that converts pancreatic trypsinogen to its active form trypsin. This
enzyme cleaves peptide bonds and also activates other pancreatic digestive zymogens-
chymotrypsinogens and procarboxypeptidases. This cascade-like action serves to protect
the pancreas from autodigestion. These pancreatic proteases work in concert with intes-
tinal peptidase, elastase, and collagenase to further break down proteins to peptide frag-
ments, di- and tripeptides, and single amino acids. Individual amino acid uptake occurs
along the brush border membrane through a variety of sodium-dependent transporters.
These transporters have a specific affinity for each amino acid based in part on their
electrochemical properties—neutral, dibasic, acidic, or imino. Di- and tripeptides are
carried independently across the brush border membrane by a group of substrate selective
carriers. Oligopeptides are also capable of being absorbed, however, once in the cytosol,
aminopeptidases break them down to their respective amino acids. The advantage of
having the capability to absorb multiple peptide configurations assures the maximal
amount of amino acid absorption. These nutrients then exit the cells through membrane
transporters and are carried directly to the liver for subsequent disposition.
    It is important to note that the rate-limiting step in dietary protein metabolism is the
intestinal absorption of amino acids. The body uses nutrient–gene interactions to regulate
the number of mucosal cell transporters in response to the dietary load of protein (7).
During periods of excessive food intake or in disease states where protein is highly
utilized, the number of mucosal cell amino acid transporters increases. The opposite
effect is seen during periods of starvation.
    Once amino acids reach the liver they can be utilized in one of three ways. The first
use is to replenish the body’s protein stores, which are continually being broken down.
The second use of amino acids is for the production of energy. The carbon skeletons of
amino acids can be converted into intermediates for the tricarboxylic acid (TCA) cycle
as well as gluconeogenesis. The last use of amino acids is in the formation of nonprotein
Chapter 4 / Nutrient Disposition and Response                                              75

compounds like nucleotides, neurotransmitters, catecholamines, hemoglobin, and albu-
min. All of these uses involve the production of ammonia by transamination or deami-
nation reactions. This toxic byproduct is converted to urea by the liver and excreted via
the kidneys.

   The average Western diet contains 60–100 g of fat daily, most of which consists of
triglycerides; the remainder is a combination of sterols, phospholipids, and fat-soluble
vitamins. The digestion of lipids begins with the secretion of pancreatic lipase. This
enzyme cleaves the 1 and 3 positions along the glycerol backbone to form two free fatty
acids and a monoglyceride. The mucosal cells of the duodenum release the hormone CCK
in response to an increased concentration of lipids. This hormone is responsible for the
release of pancreatic lipase and bile. Bile acts as an emulsifier to help with lipolysis. Once
triglycerides are broken down to their constituent monoglycerides and fatty acids, they
form bile micelles. These aggregations of bile salts and fatty acids act to orient the hydro-
phobic portions of the molecules inward and the hydrophilic portions outward toward the
aqueous environment. This orientation allows for easy movement across the watery layer
above the brush border and results in more efficient absorption. Once at the apical mem-
brane, the contents of micelles enter the cell by simple diffusion and the micelle recycles
back to the intestinal lumen. Short- and medium-chain fatty acids and glycerol are ab-
sorbed directly by mucosal cells and are transported to the portal circulation. Phospholip-
ids are absorbed in a similar fashion to triglycerides. Sterols can be absorbed directly by
mucosal cells.
   Ninety percent of the bile secreted is reabsorbed by the distal small bowel and returned
to the liver through portal blood flow. This recirculated bile can then be secreted again
or stored in the gallbladder for further use. The route of recycling bile salts is known as
the enterohepatic circulation.
   Once absorbed into the enterocytes, free fatty acids are reassembled into triglycerides
and packaged with cholesterol, phospholipids, and protein to form chylomicrons. Chy-
lomicrons act as transport vehicles for the journey through the lymphatic system. Short-
and medium-chain fatty acids are water soluble and are thus able to enter the blood by
simple diffusion.
   Those products of lipid digestion that are absorbed via the blood go directly to the liver
and are used for the synthesis of more triglycerides, cholesterols, or other compounds.
Those that are absorbed as chylomicrons reach the vascular system through the thoracic
duct and have their lipids utilized by cells all over the body or store their fatty acids in
adipose tissue. By the time a chylomicron reaches the liver all that remains are proteins
and lipid remnants. This chylomicron remnant is then absorbed by the liver and converted
into new lipoproteins.

   Vitamins are essential nutrients needed only in small amounts. They are distinguished
from carbohydrates, proteins, lipids, and minerals by the fact they are absorbed in their
natural state and by their organic nature. Historically, they have been grouped according
to their solubility. The fat-soluble vitamins are A (retinol), D (calciferol), E (tocopherols
76                                            Part I / Overview of Drug–Nutrient Interactions

and tocotrienols), and K (phylloquinone). These vitamins are absorbed in a similar fash-
ion to lipids with the help of chylomicrons and are stored in cells associated with fat.
Many require transport proteins as carriers. These vitamins generally are less readily
excreted and therefore are needed less frequently. The water-soluble vitamins are all of
the B vitamins and vitamin C. They travel in the blood and are excreted by the kidneys.
These vitamins are absorbed at various sites along the length of the small bowel by both
energy dependent and independent transport systems. Vitamin B12 requires intrinsic
factor (IF) for its absorption. IF is produced by parietal cells of the stomach. The IF-vitamin
complex travels to the terminal ileum where it is absorbed by a specific receptor. Any
compromise of IF production or the interaction between B12 and IF (i.e., gastrectomy,
pancreatic insufficiency, ileal resection) will lead to poor bioavailability of dietary B12
and subsequent deficiency. It is important to note that deficiencies are extremely rare
given the large hepatic stores of this vitamin but when present they affect multiple
systems of the body. Fortunately, a balanced diet provides adequate amounts of all
vitamins. The following is a list of vitamins, their actions, and physiologic effects of
varying concentrations:
     Thiamin (vitamin B1): Part of coenzyme thiamin pyrophosphate used for energy metabo-
     lism. Plays a role in nerve signal transduction. Deficiency is common in the homeless and
     alcoholics. Symptoms manifest as beriberi or Wernicke-Korsakoff syndrome.
     Riboflavin (vitamin B2): Part of coenzyme flavin mononucleotide (FMN) and flavin
     adenine dinucleotide (FAD) used for energy production. Found mainly in milk products,
     whole grains, and liver. Deficiency causes adenoflavinosis characterized by inflamma-
     tion of membranes of the mouth, skin, eyes, and GI tract.
     Niacin (vitamin B3): Part of coenzyme nicotinamide adenine dinucleotide (NAD) and its
     phosphate form (NADP) used for energy metabolism. Precursor is dietary tryptophan.
     Deficiency leads to pellagra characterized by “the four Ds”—dementia, diarrhea, derma-
     titis, and death. Excess supplementation causes “niacin flush.”
     Biotin: Part of a coenzyme responsible for energy and amino acid metabolism as well as
     fat and glycogen synthesis. Avidin from egg whites decreases absorption. Present in
     variety of foods and also produced by bacteria in GI tract. Deficiency leads to CNS
     symptoms, hair loss, and rash.
     Pantothenic acid: Part of coenzyme A used for energy metabolism. Present in a variety
     of foods. Deficiency includes fatigue, GI distress, and neurological symptoms.
     Pyridoxine (vitamin B6): Part of coenzymes pyridoxal phosphate (PLP) and pyridoxam-
     ine phosphate (PMP) used for amino acid and lipid metabolism. Also helps in the con-
     version of tryptophan to niacin and serotonin. Also responsible for the production of red
     blood cells. Alcohol acts as an antagonist. Deficiency leads to anemia, CNS symptoms,
     and dermatitis.
     Folate: Part of coenzymes tetrahydrofolate (THF) and dihydrofolate (DHF) used in DNA
     synthesis. Deficiency leads to anemia, GI tract deterioration. It is important in the pre-
     vention of neural tube defects during gestation.
     Cobalamin (vitamin B12): Part of coenzyme responsible for new cell synthesis, maintain-
     ing nerve cells, and breaking down amino acids and some fatty acids. Found in animal
     products. Deficiency leads to anemia, progressive nerve degeneration, and sore tongue.
Chapter 4 / Nutrient Disposition and Response                                                77

    Ascorbic acid (vitamin C): Plays roles in collagen, thyroxin, and amino acid synthesis.
    It acts as an antioxidant and helps in the absorption of iron. Found abundantly in citrus
    fruits and vegetables. Deficiency leads to scurvy, poor wound healing, atherosclerosis,
    bone fragility, and loose teeth.
    Retinol (vitamin A): Involved in vision, bone and tooth growth, maintenance of cornea,
    epithelial cells, mucosal membranes, and immunity. Found in milk and dairy products.
    Precursors are carotenoids found in leafy greens, fruits, and vegetables. Deficiency leads
    to visual problems, suppressed immune function, diarrhea, and kidney stones.
    Calciferol (vitamin D): Involved in the mineralization of bones. Synthesized by the body.
    Found in milk and dairy products and fatty fish. Deficiency leads to rickets, osteomalacia,
    and decreased calcium and phosphorous levels.
    Tocopherols/tocotrienols (vitamin E): Mainly functions as an antioxidant for lipid mem-
    brane and other components of cell. Found predominately in vegetable oils. Deficiency
    leads to erythrocyte hemolysis. Extremely high concentrations interfere with blood clotting.
    Phylloquinone (vitamin K): Involved in synthesis of blood-clotting proteins. Found in green
    leafy vegetables and also synthesized by bacteria in gut. Deficiency leads to hemorrhage.

   Minerals are inorganic compounds that are required in small amounts. They play a
vital role assisting in processes of energy production, growth, hemoglobin synthesis, as
well as the metabolism of carbohydrates, lipids, proteins, and vitamins. Minerals are
absorbed and distributed throughout the body without alteration to their chemical struc-
ture. Excess amounts can be toxic, thus the body must be careful in their absorption.
Minerals are usually divided into two groups, major and minor, depending on their
required amounts. Calcium, phosphorous, potassium, sulfur, sodium, chloride, and mag-
nesium are classified as major or macro minerals. Their requirements are often described
in grams. Iron, zinc, copper, manganese, iodine, and selenium are considered minor or
trace minerals and their requirements are measured in milligrams to micrograms. A
normal balanced diet adequately supplies all required amounts of minerals. The follow-
ing is a brief description of a few minerals.
   Iron is absorbed from vegetables (non-heme iron) and meats (heme iron). The average
dietary intake is 10–20 mg/d with men absorbing 1–2 mg/d, whereas menstruating women
and iron-deficient people absorb 3–4 mg/d. Heme iron is the more readily absorbed of the
two (10–20 vs 1–6%). Heme iron requires only the presence of gastric acid to expel the
globin molecule. Non-heme iron requires gastric acid and other luminal agents like ascor-
bic acid to convert it from a ferric to ferrous configuration. Ferrous iron is readily soluble
and more easily absorbed. Dietary factors such as phosphates, phytates, and phosphop-
roteins can render non-heme iron insoluble and impair its absorption.
   Both dietary forms of iron are mainly absorbed by the duodenum. Some iron remains
in enterocytes as ferritin while the remainder is transported through the blood bound to
transferrin. Iron is lost on a daily basis through the exfoliation of mucosal cells. A
deficiency in iron is manifested by anemia (microcytic), a decrease in serum ferritin, and
increase in serum transferrin levels. Iron overload can be toxic. The genetic disorder
hemosiderosis leads to iron deposits in the liver and eventual cirrohsis.
78                                            Part I / Overview of Drug–Nutrient Interactions

   Zinc plays a variety of roles throughout the body including maintaining pancreatic
function, wound healing, enzymatic reactions and blood clotting. Only about 15–40% of
dietary zinc is absorbed. Various transporters have been identified for the absorption of
zinc, but the exact mechanism still remains incomplete (8). Certain animal proteins have
been shown to modulate zinc absorption. Phytates have been shown to chelate zinc and
prevent its absorption.
   Phosphorous is the second most abundant mineral in the body. The vast majority is
bound to calcium in teeth and bones. It is predominantly absorbed in the upper small
intestine by a sodium cotransport system present on the apical surface of brush border
cells. The transport system is highly dependent on vitamin D for its activity. There are
no known dietary deficiencies of phosphorous because it is so ubiquitous in the food
   Calcium absorption is concentration dependent (9). During periods of low calcium
ingestion, active absorption occurs in the duodenum. Vitamin D plays an important role
in transporting calcium out of enterocytes and into the vascular system. During periods
of moderate to high calcium ingestion, the mineral is absorbed by passive diffusion in the
jejunem and ileum. The regulation of calcium blood levels falls under the control of
parathyroid hormone. An increase in this hormone leads to increased intestinal absorp-
tion, decreased renal excretion, and increased bone metabolism.

   The average person ingests 1–2 L of fluid a day plus an additional 6–7 L from GI
secretions. Therefore, the body must be able to absorb large quantities of water. By the
time ingesta reaches the large intestine, 80% of water has been absorbed (10). Osmotic
gradient is the principle by which water is absorbed. The absorption of water is dependent
on the absorption of solutes, in particular sodium and glucose as part of the transporter
SGLT-1. The absorption of nutrients results in a large accumulation of sodium and other
molecules on the anti-luminal side of enterocytes. This causes a high osmotic gradient
toward which water flows. The net result is movement of water between the tight junc-
tions of enterocytes and into the blood. As water moves farther down the GI tract, the tight
junction becomes less permeable. Water becomes more dependent on sodium absorption.

10.1. Aging
   The effects of aging can have a profound influence on the digestion and absorption of
nutrients. Aging can impair memory, cognition, and vision, all of which make initiating
food intake difficult. Tooth loss and decreased sensory input make the act of eating less
enjoyable. The metabolic demands of the body change and metabolism declines. Older
people have less muscle mass and increased fat, thus protein and carbohydrate consump-
tion take precedence over fats in the diet. An older person has less total body water content
and therefore is more easily subject to dehydration. Vitamin deficiencies are more preva-
lent in older people. B12 deficiency is common because of the increased incidence of
atrophic gastritis. As it ages, the body is less able to synthesize the active form of vitamin
D. Deficiencies in vitamin D are more common and are a result of decreased intake
Chapter 4 / Nutrient Disposition and Response                                                    79

coupled with the body’s inability to synthesize the active form. Osteoporosis leads to
calcium deficiencies. Iron-deficiency anemia is also a common problem found in older
people secondary to decreased production of HCl by the stomach. These absorptive
problems are often exacerbated by the presence of other comorbid diseases, the use of
multiple medicines, or rigid learned dietary habits.

10.2. Disease
   The effect of various diseases on absorption and digestion results in malnutrition and
ultimately severe illness. Disease can be found along the entire GI tract and may result
from genetic, infectious, or iatrogenic causes. These alterations can affect the luminal
factors involved in digestion or impair the function of the brush border cells in absorption.
Genetic diseases like cystic fibrosis and lactase deficiency are common throughout the
world. Inflammatory conditions like pancreatitis, gastritis, and inflammatory bowel dis-
ease also lead to impaired nutrient absorption. Bacterial overgrowth and commonly
acquired conditions like celiac disease, diabetes, and infectious gastritis also lead to
impaired nutrient uptake. A variety of surgical procedures including gastric resection,
short bowel syndrome, ileostomy, or colostomy lead to altered nutrient absorption. It is
also important to note that diseases affecting other organs like the kidneys, the liver, and
gallbladder can also have an effect on nutrient digestion and absorption.

   The absorption and digestion of nutrients is a complex and highly coordinated process.
Interactions between the CNS and peripheral nervous systems as well as the GI tract must
act in concert to assure that metabolic demands are met. In an effort to better elucidate
the effects of a multitude of diseases involving the GI tract as well as the interventions
preformed upon it by the medical community, it is paramount that we understand the roles
that chemical messengers, GI hormones, digestive enzymes, and mechanical stimuli
play. We must always remember when caring for patients that age, disease processes, and
altered physiologic states have profound effects on the milieu of nutrient assimilation. An
understanding of the workings of each component, as an individual entity and in the
overall picture, will allow for better care of patients. Future efforts in appreciating DNIs
will require this level of knowledge.

 1. Allen L, Billington C. Why do we eat? a neural systems approach. Annu Rev Nutr 1997;17:597–619.
 2. Schwartz MW, Woods SC, Porte D Jr., Seeley RJ, Baskin DG. Central nervous system control of food
    intake. Nature 2000;404:661–671.
 3. Schwartz MW, Baskin DG, Kaiyaka KJ, Woods SC. Model for the regulation of energy balance and
    adiposity by the central nervous system. Am J Clin Nutr 1999; 69:584–596.
 4. Cullen J, Kelly K. Gastric motor physiology and pathophysiology. Surg Clin North Am 1993;73(6):
 5. Horowitz M, Dent J, Fraser R, Sun W, Hebbard G. Role and integration of mechanisms controlling
    gastric emptying. Dig Dis Sci 1994;39(12 Suppl):7S–13S.
 6. Greenfield L, Mulholland MW, Lillemoe KD, Oldham KT, Zelerock GV, eds. Surgery: Scientific
    Principles and Practice. Lippincott-Raven, Philadelphia, PA, 1997.
 7. Stipanuk M. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia, PA, W.B.
    Saunders, 2000.
80                                              Part I / Overview of Drug–Nutrient Interactions

 8. Lonnerdol B. Dietary factors influencing zinc absorption. J Nutr 2000;130:1378S–1385S.
 9. Bronner F. Calcium absorption: a paradigm for mineral absorption. J Nutr 1998;128:917–920.
10. Whitney E, Cataldo C, Rolfes S. Understanding normal and clinical nutrition. Wadsworth/Thomson
    Learning, Belmont, CA, 2002.
Chapter 5 / PCM and Drugs                         81

82   Part II / Influence of Nutritional Status
Chapter 5 / PCM and Drugs                                                                83

     5           The Impact of Protein-Calorie
                 Malnutrition on Drugs

                 Charlene W. Compher

   Nutritional factors may influence the absorption, metabolism, distribution, and clear-
ance of medications. This chapter focuses on malnutrition and its impact on the safe and
effective management of medications. The scope of this chapter does not extend to a
consideration of the effects of particular drugs on nutritional status.

1.1. Malnutrition
   Malnutrition may be a chronic or acute problem, and primary or secondary to other
processes (1). Chronic starvation, resulting from inadequate food supply, results in pro-
tein and energy deficiency, a syndrome known as protein-energy malnutrition (PEM) or
protein-calorie malnutrition (PCM). When the predominant deficiency is chronic
undersupply of calories, the syndrome is called marasmus, as evidenced by extreme,
unintentional weight loss or severe growth failure in children (1). When the predominant
deficiency is protein intake, the syndrome is called kwashiorkor, with attendant loss of
muscle mass, often with ascites or edema. Some individuals may have combined defi-
ciencies of protein and calories, termed marasmic–kwashiorkor (1).
   Malnutrition in children is defined by comparison to World Health Organization/
National Center for Health Statistics (WHO/NCHS) weight and height standards (1,2).
Underweight is defined as a child who is more than 2 standard deviations below the
weight-for-age reference range. Wasting is defined as a child whose weight-for-height
is more than 2 standard deviations below the reference. Finally, a height-for-age more
than 2 standard deviations below the reference indicates stunting (1,2).
   Severe marasmus, kwashiorkor, and marasmus–kwashiorkor are seen in Western
health care facilities, particularly in very ill, elderly patients. However, the more usual
pattern in the general population occurs in normal, overweight or obese patients prior to
hospital admission (3). Weight loss during hospitalization is common, as is rapid devel-
opment of severely depleted serum protein levels in response to injury, infection, surgi-
cal, or medical treatments, and prolonged limited intake of protein (4).
   Although protein and energy status have classically defined the syndrome, in the most
typical presentation with starvation, the entire food supply is limited such that deficien-
                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
84                                                    Part II / Influence of Nutritional Status

cies of many other nutrients occur simultaneously (1). A relatively recent observation in
developing countries is increasing obesity concurrently with prevalent PEM. Obesity
occurs when caloric supply is sufficient to promote chronic diseases (diabetes, hyperten-
sion, and cancer) but the nutrient content of the diet is poor (5).
   The prevalence of primary PEM is greatest in developing countries, particularly where
famine occurs following natural or manmade disasters (1). Worldwide, 800 million
people from developing countries are undernourished, a figure that includes 193 million
(36%) underweight, 230 million (43%) stunted in growth, and 50 million (9%) wasted
children below the age of 5 (1). The prevalence of underweight children is 36% in all
developing countries, with a range from 11% in Latin America to 60% in South Asia (2).
The percentage of infants born small (<2500 g) is 19% in all developing countries, with
a range of 11% in Latin America and East Asia to 34% in South Asia (2). Although the
overall percentage of malnourished children has been reduced in countries with eco-
nomic and political stability, the actual total number is unchanged owing to burgeoning
population growth. When natural disasters, such as droughts, floods, earthquakes, or
famine occur, the prevalence of PEM in a developing country may be increased. Simi-
larly, when manmade disasters such as wars, political upheavals, or economic crises
occur, malnutrition prevalence in the population is exacerbated (1).
   The age groups at greatest risk of PEM are those with increased nutritional needs for
growth, reproduction, or milk production—infants and pregnant or lactating women—
(1,2), and the elderly (4). Maternal malnutrition peri-pregnancy is a key factor in the birth
of an underweight newborn, and its development into a child with PEM (1). Although
marasmic malnutrition (wasting) is most common in children under 1 yr of age, weaning
from breast milk later on is associated with kwashiorkor malnutrition when the available
diet contains much lower protein content than milk. The elderly are particularly suscep-
tible to PEM when their medical or socioeconomic status limits their ability to obtain and
ingest nutritionally adequate diets (4,6,7).
   The prevalence of PEM is generally thought to be greater in rural than urban popula-
tions in developing countries, although urban prevalence is unacceptably high. In Tur-
key, stunting in children is 20.5% in rural vs 16.1% in urban children (8). In Nigeria,
41.5% of rural children under 5 yr have PEM (9) vs 37.9% in an urban population (5). The
rapid increase in population growth in cities in developing nations often comes with
limited planning and many health problems. The prevalence of malnutrition has not been
substantially reduced in part due to extreme poverty, poor housing conditions, limited
parental involvement in food preparation (parents working at low-paying jobs), and
violence (5).
   The prevalence of vitamin and mineral deficiencies can outpace actual PEM preva-
lence. In Turkey, the prevalence of PEM in cities is 20%, however, iron-deficiency
anemia is seen in 50% of preschool children, pregnant and lactating women, and in 33%
of school-age children (8). Deficiencies of iodine and vitamin A are also common.
   Severe primary PEM is occasionally reported in developed countries in the setting of
unusual dietary practices. Case reports of four children with PEM in the United States
were associated with intake of a rice beverage as an alternative to milk, on the basis of
suspected food allergies (10). Another 12 cases of frank kwashiorkor in children 1–22 mo
Chapter 5 / PCM and Drugs                                                                 85

old were referred to dermatologists over a 9-yr period in seven tertiary referral centers in
the United States based on complaints of edema and flaky paint dermatitis, classic signs
of kwashiorkor (11). These cases were attributed to the substitution of low protein fluids
for milk or formula, owing to a combination of perceived or true milk allergy, food
faddism, or nutritional ignorance. Financial or social stresses were a factor in only 2 of
the 12 cases (11).
   Severe PEM in developed countries is more commonly secondary to disease processes
or their treatments, which limit adequate oral nutrient intake or increase nutritional
requirements or losses (12). This may be the result of a reduced ability to take adequate
diet (such as cancers causing obstructions of the intestinal tract) or change in mental
status (such as cerebrovascular accident, head injury, dementia, or severe dehydration).
The ability to absorb nutrients may be compromised, as with malabsorption syndromes,
cystic fibrosis, or intestinal infections. Other diseases or hospital treatments may increase
nutrient requirements, typically significant infections, pulmonary diseases, acute injuries,
surgery, and intensive chemotherapy or radiation therapy to treat malignancy. Nutrient
losses may occur owing to changes in metabolism, cellular destruction in response to
chemotherapy, or accelerated excretion.
   Children with cancer have greater prevalence of PEM than healthy children in the
population. In 65 children who presented to an outpatient setting for cancer therapy, 25%
were at nutritional risk, with equal proportions of malnutrition and obesity (12). By
contrast, of those hospitalized for cancer treatment, 45% (41/91) were nutritionally at
risk. Of these, 83% were malnourished and 17% were obese (12). In an evaluation of all
1033 children diagnosed with acute lymphocytic leukemia in the United Kingdom between
1986 and 1991, wasting was prevalent at the time of diagnosis in 7.6% of boys and 6.7%
of girls (13).
   Children with chronic diseases also have a remarkable prevalence of malnutrition.
PEM has been described in 36–50% of two cohorts with juvenile rheumatoid arthritis in
the United States (14). In a group from Mexico, 14.7% of children in a cohort with
rheumatoid arthritis or rheumatic fever were underweight by WHO/NCHS criteria, but
albumin concentration was normal (14).
   For adult patients living independently at home, the prevalence of malnutrition is 1–8%,
whereas the prevalence for institutionalized individuals rises to 25–60% (4). This increased
prevalence in institutionalized patients in part reflects health care decision making that
supports keeping in institutions seriously ill individuals with complicated medical condi-
tions. For hospitalized patients, the prevalence of malnutrition ranges from 35 to 65%,
where higher acuity, critically ill patients also have more signs of malnutrition (4,7).
   In developed countries, milder forms of malnutrition and obesity may be associated
with food insecurity. The term food insecurity describes the difficulty that relatively
impoverished groups in the population have in obtaining optimal food intake throughout
the entire month, and during irregular circumstances. Food insecurity is a chronic prob-
lem, particularly among the 2.5–3 million homeless Americans (15). Food insecurity is
generally associated with adequate caloric supply but poor food quality, leaving affected
individuals susceptible to the development of low-grade vitamin and mineral deficien-
cies. Food insecurity fell by 11.3% and the prevalence of hunger fell by 15.6%, adjusted
86                                                    Part II / Influence of Nutritional Status

for population growth, between 1998 and 2000 (15). Federal food assistance programs
were used by 50% of food-insecure households, whereas private food banks or churches
provided food to 16.7% of the food insecure, a total of 2.4% of total US households (15).
   PEM is consistently associated with increased mortality, and often with infections.
PEM is associated with 56% of all deaths of children aged 6 to 59 mo, where their death
is attributed to the added impact of malnutrition on infectious disease (1). Acute respi-
ratory infections are associated with 30.3% of deaths in children, as well as a large
proportion of deaths due to measles, pertussis, and HIV–AIDS (2). In Malawi, 75% of
admissions to nutrition rehabilitation centers are for kwashiorkor or marasmic–kwash-
iorkor, with a typical 20–30% mortality (16). In 250 children admitted for care, 34%
were HIV positive, with 62% having marasmus and another 35% marasmic–kwash-
iorkor. The mortality was increased 1.6-fold in HIV-positive relative to HIV-negative
malnourished children (confidence interval [CI] = 1.14–2.24). The authors cited limited
food supply and nursing resources in the rehabilitation centers as unfortunate factors in
the mortality rates (16).
   In patients who are cared for in US medical facilities, malnutrition has been associated
with poor clinical outcome and increased cost of medical care for 70 yr. Unintentional
loss of more than 20% body weight predicted a threefold increase in mortality and
morbidity in surgical patients with benign gastric ulcers (17), whereas the frequency and
severity of postoperative infection prior to antibiotics depended on the protein reserve of
the patient (18). In 87,078 consecutive surgical cases from 44 Veterans Affairs medical
centers, of 54,215 patients who had a preoperative albumin concentration, albumin was
negatively correlated with postoperative mortality regardless of risk associated with the
particular surgical procedure (19). Albumin concentration below the normal range was
associated with a 1.5- to 9-fold risk of nosocomial infection and a 1.3- to 1.5-fold increase
in length of hospital admission (20). Hospitalized patients who are malnourished consis-
tently have increased mortality and morbidity (3,5,6,8–10,15–20).
   Thus, at the current time, health care facilities are required by the Joint Commission
for Accreditation of Healthcare Organizations (JCAHO) to develop and implement a plan
for screening all patients for nutritional risk. Although the specific details of the nutri-
tional screen vary among facilities, based on typical patient populations and laboratory
assay methods, at least three factors are usually included. The first is unintentional weight
loss or visible body wasting. The second factor includes difficulty with food ingestion or
absorption, based on food availability and concurrent disease processes. The final factor
is an assessment of serum protein concentrations, most commonly albumin.

2.1. Physiologic Changes With Varying Degrees of PEM
  Because PEM develops gradually over weeks to months, a series of metabolic and
behavioral adaptations occur, with the aim of preserving limited body tissue (21). With
prolonged severe limitations in nutrient intake, however, the process of adaptation is not
successful and the patient succumbs, usually to death from an otherwise minor infection (1).
  Dramatic changes in body composition herald significant malnutrition. A loss of
subcutaneous body fat stores occurs, leaving visible bony prominences.
Chapter 5 / PCM and Drugs                                                                87

   Protein catabolism leads slowly to muscle wasting (3,21), which can be detected in
adults by squared off shoulders and limited biceps mass. With severe disease, visceral
protein depletion (including reductions in serum albumin and total protein) results from
reduced protein synthesis, leading to edema and ascites (21).
   With marasmic malnutrition, body fat stores are reduced and total body water increased,
as measured by body composition. In a five-compartment model, fat mass is 22%, extra-
cellular water 21%, intracellular water 39%, protein 15%, and minerals 2% during nor-
mal nutritional states. By the point of marasmic malnutrition, the fat mass has been
reduced by two-thirds, and the extracellular water expanded 50% (11).
   When gradual starvation is not complicated by infection, the body reduces its produc-
tion of less essential proteins, such as growth and sex hormones, insulin, and thyroid
hormone (21). The reduction in thyroid hormone causes a significant decline in metabolic
rate and thus energy expenditure. Body cell mass, including red blood cells, T-lympho-
cytes, and complement are reduced, leading to anemia and fatigue. Reduced immune
surveillance, in the setting of an overcrowded, unhygienic environment leaves malnour-
ished individuals at far greater susceptibility to infection (3,21). The production of
enzymes, including those with a role in drug metabolism, is also reduced (22–28).
   The adaptive processes include reduced resting energy expenditure resulting from loss
of metabolically active tissue, and reduced energy expenditure for activity as the mal-
nourished individual is too weak for physical exertion, and reduced thermic effect of
feeding as caloric supply is limited (21). Thus, daily total energy expenditure is reduced.
   Gradual loss in organ function occurs with prolonged, severe malnutrition (21). Blood
glucose concentration is initially maintained by the autocatabolism of body fats to glyc-
erol (and free fatty acids) and of gluconeogenic amino acids. With severe or end-stage
PEM or when severe infections limit hepatic function, blood glucose concentrations may
drop. Total body potassium and zinc are lost with muscle catabolism. Cardiac output,
heart rate, and blood pressure are decreased, with reduced venous return. Renal plasma
flow and glomerular filtration rate are limited secondary to reduced cardiac output, but
water and electrolyte clearance are unchanged. Diarrhea is common with PEM, for vari-
ous reasons including limited intestinal secretions, bacterial overgrowth, nutrient defi-
ciencies (particularly of vitamin A or zinc), and villous atrophy (21). Hepatomegaly is
associated with steatosis, as nutrient deficiencies prevent the export of fat from hepato-
cytes. Hepatic production of serum proteins (albumin, prealbumin, and transferrin) is
reduced with continuing malnutrition, as are hemoglobin and hematocrit (21).
   After the development of severe malnutrition, whether primary or secondary, patients
are susceptible to refeeding syndrome during the early hours to days of their nutritional
rehabilitation. This syndrome of acute declines in extracellular concentration of potas-
sium, magnesium, and phosphorus occurs as these electrolyte and mineral elements shift
intracellularly with glucose, in response to insulin secretion with feeding (29). Two
fatalities have been attributed to severe hypophosphatemia in the setting of overzealous
parenteral refeeding, although hypokalemia may also have been a factor (29). Thus, it is
safest to restore nutritional deficits slowly, limiting glucose supply for several days, and
carefully repleting electrolytes as indicated by serum concentrations. Because cardiac
function may be impaired and fluid shifts can occur rapidly with refeeding, diuretics
should be given when needed.
88                                                   Part II / Influence of Nutritional Status

   Nutrients supplied to the malnourished patient during refeeding can impact drug
metabolism. High protein intake induces the microsomal or mixed function oxidase
system (MFOS), which can alter the half-life of medications (30). Carbohydrates have
limited impact on drug metabolism, however aggressive carbohydrate intake may exac-
erbate refeeding syndrome, with attendant electrolyte shifts that can secondarily impact
drug toxicity (see Subheading 2.3.3.). Deficiencies of essential fatty acids, which can
occur with limited intake of linoleic or linolenic acid in as short a time as 2 wk, are
associated with reduced activity of MFOS in the hepatic endoplasmic reticulum (29).
Thus, refeeding with fatty acids, intravenous lipid emulsion, or dietary corn oil, can
stimulate the MFOS.
2.1.2. ALCOHOL
   Alcoholics, particularly those admitted with acute intoxication or withdrawal, often
have PEM, including weight loss, limited muscle mass, and fat mass (31). Regardless of
liver disease, continued alcohol consumption has been associated with weight loss,
whereas abstinence produces weight gain. Some patients do not appear chronically
malnourished, however, when daily alcohol intake is more than 30% of total kcal, nutri-
ent intake of protein, fat, vitamins A, C, and thiamin, and calcium, iron and fiber are less
than desirable (31). Vitamin D deficiency is common and results in low calcium, phos-
phorus and magnesium levels. Vitamin K deficiency can arise with fat malabsorption
(pancreatic insufficiency, biliary obstruction, or mucosal damage owing to folate defi-
ciency). Folate deficiency is common (37.5%) in active drinkers, likely resulting from
increased urinary and fecal losses and to limited hepatic vitamin retention (31). Vitamin
B12 deficiency may occur secondary to pancreatic insufficiency, limiting the release of
the vitamin from its protein carrier in the intestinal lumen. Up to 50% of alcoholics may
have subtle riboflavin deficiency. Magnesium and zinc status are generally reduced in
alcoholics, in part due to increased urinary excretion magnesium and marginal intake of
zinc. Iron deficiency may occur due to gastrointestinal bleeding, but excess hepatic iron,
copper, and nickel stores are also seen with cirrhosis (31).
   Alcohol impairs digestion and absorption (diarrhea, motility changes, folate defi-
ciency, alcoholic pancreatitis, bile salt deficiency), which may also limit drug absorption.
Ethanol impairs hepatic amino acid uptake and synthesis of lipoproteins, albumin, and
fibrinogen (31), perhaps reducing protein carrier availability. In animal studies, the
cytochrome P450 (CYP) system is induced by alcohol ingestion, a factor that speeds
the clearance of other CYP-metabolized drugs and nutrients (e.g., vitamins A and C).
Ethanol-induced vitamin A depletion is associated with reduced detoxification of
xenobiotics (32).
2.2. Animal Experiments
    A series of animal experiments were designed to examine specific aspects of the
impact of severe malnutrition on drug handling. Experiments conducted prior to 1972
verified consistently that oxidation rates of drugs were reduced with significant malnu-
trition (23). More recent experimental findings are discussed in the following sections.
  Salicylate ototoxicity was enhanced with magnesium and zinc deficiencies (33). Zinc
deficiency also enhanced a reversible salicylate-induced nephrotoxicity (33).
Chapter 5 / PCM and Drugs                                                               89

   A limitation in protein carriers, which occurs commonly with PEM, reduced chloram-
phenicol distribution in rats. Hypoproteinemic rats, given a single dose of chlorampheni-
col, had higher drug concentration, with greater renal than hepatic drug distribution, and
diminished plasma half-life (34). The authors speculated that reduced protein binding of
the drug allowed the higher drug levels and the shortened half-life.
   During malnutrition, the metabolism of chloramphenicol is reduced. In guinea pigs fed
a protein-depleted diet, total body and liver weight (but not hepatocyte number) were
reduced (35). Hepatic microsomes had reduced conjugation of chloramphenicol, due to a
reduced uridine diphosphate (UDP)-glucuronidase activity per cell, and reduced response
to induction by 3-methylcholanthrene (35). These data suggest that the increased drug
levels of chloramphenicol in malnourished patients may in part be owing to reduced drug
clearance by the liver (35). In malnourished rats treated with chloramphenicol, hepatic
microsomal aniline hydroxylase and aminopyrine-N-demethylase activities were mark-
edly reduced (36). Mitochondrial oxidative phosphorylation, which was already inhibited
by PEM, was further potentiated by chloramphenicol treatment.
   Gentamicin ototoxicity was enhanced with experimental magnesium and zinc defi-
ciencies (33). With magnesium deficiency, the hearing loss induced by gentamicin treat-
ment was nearly complete and irreversible in 9 out of 25 (36%) rats. Magnesium
deficiency can induce hearing loss independently of gentamicin, owing to low extracel-
lular magnesium concentrations allowing influx and turnover of Na+, K+, and Ca++, with
a resulting reduction in cochlear blood flow (33). Enhanced membrane permeability of
the hair cells and thus increased ion pumping was the most likely mechanism behind
increased ototoxicity with zinc deficiency (33). Experimental dietary potassium deple-
tion in the dog was associated with increased gentamicin nephrotoxicity, with the drug
concentrated in the renal cortex of potassium-depleted animals (37). Gentamicin admin-
istration also induced urinary potassium wasting (37).
   To examine the impact of malnutrition on sulfadiazine acetylation by the hepatic phase
II conjugation pathway, a rhesus monkey model was employed (38). States of normal
nutrition, PEM, and nutritional rehabilitation were induced by change in quantities of
diet. Total absorption of sulfadiazine was unchanged, although the peak was delayed in
the group with PEM. The peripheral volume of distribution of the drug was reduced, as
were the elimination rate constant and clearance rate. These latter two factors resulted in
increased drug half-life and drug area under the concentration-time curve (AUC) in the
group with PEM. Acetylation was only measured in hepatic tissue (representing 33% of total
acetylation), and appeared unchanged by PEM. The authors suggested that the reduced
volume of distribution of drug may be a key factor in reducing drug elimination (38).
   Isoniazid (INH) hepatotoxicity was examined in an experiment with caloric depriva-
tion, PEM, and usual diet in rats (39). After 2 wk of INH, all animals had transaminitis,
90                                                    Part II / Influence of Nutritional Status

and proliferation of the rough endoplasmic reticulum in liver tissue. Glutathione activity
was reduced in both liver and blood samples, suggesting reduced free radical defense.
The INH-induced loss of glutathione activity was further exacerbated by concurrent
malnutrition (39). Similar findings were noted in a related experiment testing both INH
and rifampicin (40).

   Changes in drug disposition may vary with the degree of PEM. In severe PEM, drug
absorption may be reduced, protein carriers limited, and metabolism slowed, resulting in
higher drug concentrations and a potential for toxicity with drugs that have a narrow
safety margin. In mild to moderate malnutrition, changes in metabolism may be minimal
or of limited clinical significance, however, the clinical data to support this conclusion
are very limited.

3.1. Absorption
   The physical properties of medications, such as lipid-solubility, molecular weight,
acidity, and biopharmaceutical properties impact their absorption (22–28). During PEM,
however, absorption may be reduced as a result of physiologic changes, particularly in
children with severe PEM and in alcoholic adults (31).

3.2. Distribution
   In later stages of malnutrition, when hepatic protein synthesis is reduced, protein
carriers for drugs may be limited, resulting in greater concentrations of free drug avail-
able for tissue use or elimination (22–28). In established kwashiorkor, both extracellular
fluid accumulation and low serum albumin concentrations prevail (1,21), and may be
exacerbated by the liver’s inflammatory response to infection further reducing albumin
synthesis. In addition to a reduction in carrier availability, the associated fluid shifts and
edema may impact drug concentrations or tissue distribution.

3.3. Metabolism
    Clinical reports to date have described a different pattern in the impact of malnutrition
on drugs depending on the severity of malnutrition (22–28). Reports in children have
primarily reflected severe PEM (marasmus, kwashiorkor, or marasmic–kwashiorkor)
with most children from India or Africa. In the few published adult studies, subjects have
been mildly to moderately malnourished, likely of shorter duration, and in very small
subject numbers. With the milder forms of malnutrition, oxidative metabolism of drugs
is reported as unchanged or increased. By contrast, when the malnutrition has progressed
to kwashiorkor, metabolism is consistently reduced.
    Antipyrine is a compound exclusively metabolized by the liver, with very limited
hepatic extraction, and is a suitable marker of MFOS activity (41). The drug is protein-
bound to a limited degree and its elimination and distribution are not impacted by hypoal-
buminemia. In a group of 45 adult patients with inflammatory bowel disease, who had
suffered more than 10% weight loss and/or reduction in albumin concentration (30 g/L,
vs 40 g/L in 25 normal controls), CYP activity was evaluated by antipyrine metabolism
(41). Overall metabolic clearance was reduced, but weight-corrected clearance was
unchanged. In 27 of these patients, who were restudied after 30 d of nutritional reple-
Chapter 5 / PCM and Drugs                                                                91

tion, clearances were normalized in those who had protein malnutrition but unchanged
when the initial deficit was caloric (41).
   In 30 undernourished adults hospitalized with peptic ulcer disease or abdominal pain
and only mild hypoalbuminemia, liver biopsy specimens were evaluated for aryl hydro-
carbon hydroxylase (AHH) and CYP concentrations (42). CYP was unchanged, but AHH
increased in the undernourished men, a pattern suggesting increased ability to activate
reactive metabolites concurrent with reduced ability to detoxify them.

3.4. Excretion
   Renal clearance of drugs may be impacted by protein intake. Because renal tissue is
spared until very severe stages of malnutrition, however, most reports to date do not
report reduced renal drug clearance with PEM. The possibility that concurrent clinical
comorbidities (e.g., hypertension, diabetes, renal disease) may play a role in altered renal
drug clearance, particularly in elderly or metabolically stressed critical care patients,
should be considered.

3.5. Drug Effects
   The therapeutic effectiveness of a drug may be reduced or the prevalence of toxicity
increased because of malnutrition. When absorption is reduced and/or excretion increased,
adequate drug levels in serum or tissues may not be achieved. When the half-life of a drug
is prolonged, owing to reduced hepatic metabolism or renal elimination or increased
volume of distribution, toxic drug or drug metabolite levels can occur. In malnourished
subjects, drugs with a narrow safety margin can produce toxicity at usual dosage levels
if the drug’s bioavailability is increased because of impaired hepatic function (28).
However, if the toxicity of a given drug results from its metabolite, then the slowing of
CYP activity may actually reduce toxicity (28).

3.6. Drug-Specific Clinical Evidence
   The clinical evidence is rather limited in terms of number of drugs tested,the range of
malnutrition described, and is composed almost entirely of pharmacokinetics data from
very small numbers of subjects. Thus, negative findings may be based on sample sizes
too small to state with any confidence that there is no difference.
   Acetaminophen (paracetamol) is easily absorbed, rapidly distributed, has insignifi-
cant protein binding, and is metabolized to glucuronide and sulfate products eliminated
renally (28,43). In children with severe PEM, the biotransformation of acetaminophen
was reduced, as evidenced by a prolonged half-life and reduced elimination. The authors
suggested monitoring drug levels to avoid toxicity in patients with severe PEM (43). By
contrast, in adults with milder PEM, acetaminophen toxicity was not greater than in
subjects with normal nutritional status, even with coadministration of vitamin C (23).
Acetaminophen pharmacokinetics were unchanged during a 5-d 500 kcal/d deficit diet
in six obese subjects and during a 13-d 1000 kcal/d deficit diet in three obese patients, in
a cross-over design study (44). Both of these studies in adults (43,44), however, were
seriously underpowered to detect a significant difference, if one existed.
   The impact of moderate malnutrition in children with rheumatoid arthritis or rheu-
matic fever on salicylate pharmacokinetics was examined (14). The biotransformation of
92                                                    Part II / Influence of Nutritional Status

salicylate and its AUC were reduced, relative to normally nourished controls. The authors
suggest kinetic modeling of salicylates in patients with even moderate malnutrition (14).
3.6.2. ANTIMICROBIALS Chloramphenicol. For the treatment of community-acquired pneumonia in
Gambian children under age 5 yr, oral chloramphenicol was prospectively compared to
trimethoprim-sulfamethoxazole in a randomized clinical trial (45). In 111 children with
marasmic malnutrition, the two antibiotic regimens performed similarly to normally
nourished controls, with 16 treatment failures in each group. The 32 treatment failures
were slightly more malnourished (weight 59.3% standard vs 60.7%) than the 79 treat-
ment responders and had a higher percentage of positive blood or lung aspirate cultures
(31 vs 13%, p < 0.05). Serum proteins were not measured (45). This study illustrates the
difficulty in separating the impact of malnutrition alone from that of concurrent infection.
   In 33 Ethiopian children aged 0.6 to 6 yr, nutritional status was determined to be
normal in 8, marasmus in 8, kwashiorkor in 8, and marasmic–kwashiorkor malnutrition
in 9 children (46). Chloramphenicol absorption was erratic, with 30% absorption in
patients with marasmic–kwashiorkor and 44% with kwashiorkor. With kwashiorkor, the
clearance of chloramphenicol was reduced to approximately half normal, the half-life
prolonged and effective drug concentration increased. The authors suggest individual
drug monitoring owing to the great interindividual variation in pharmacokinetics (46).
   Chloramphenicol clearance was reduced after its incomplete metabolism in malnour-
ished Ethiopian children (47). The 34 children, ranging in age from 9 mo to 10 yr, were
screened into three categories of malnutrition. Fourteen were underweight with normal
serum protein, 10 were marasmic with slightly reduced serum protein, and 10 had kwash-
iorkor with marked reduction in serum protein concentration. Unbound chloramphenicol
and chloramphenicol succinate were increased in serum, particularly in those with kwash-
iorkor, where the albumin concentration was significantly reduced. Chloramphenicol
monosuccinate clearance was reduced owing to limited nonrenal clearance, and the
fraction of prodrug excreted unchanged in the urine ranged from 0 to 51% (median 17%).
The AUC of chloramphenicol was doubled in the children with marasmus and tripled in
those with kwashiorkor, relative to those who were underweight. The authors suggest that
if drug monitoring is not possible, measurement of serum total protein may assist in
screening for patients who need dosage adjustment (47).
   By contrast to the data with malnourished children, chloramphenicol metabolism was
not significantly changed from controls with normal nutritional status in six undernour-
ished adults (48), despite a significantly lower albumin concentration (29.7 g/L vs 42 g/L
in normals). Replication of this study in a larger cohort would help to clarify whether there
really is no difference or perhaps the study simply lacked statistical power. Gentamicin. Gentamicin, an aminoglycoside antibiotic with a frequent renal
injury profile, is commonly used for Gram-negative coverage in pediatric practice (49).
In 11 malnourished 3- to 10-mo-old infants, gentamicin was metabolized and eliminated
normally, but its volume of distribution was increased, likely because of increased total
body water, which had replaced muscle mass with starvation (49). In a second group of
six malnourished children aged 4–14 yr, gentamicin was reported as not different from
normally nourished controls (50). The half-life was almost doubled, the clearance nearly
halved, and the maximal concentration increased 20%. The number of subjects was very
Chapter 5 / PCM and Drugs                                                                 93

limited and the standard deviations very large, thus these differences were not statisti-
cally significant (50). In a third group of six children with severe kwashiorkor, adequate
gentamicin concentrations were achieved, although its half-life was prolonged (51).
Nutritional rehabilitation was associated with normalization of gentamicin half-life—a
surrogate marker for clearance (51).
    In 86 critically ill adult patients, those who had malnutrition (defined as low albumin
and >15% weight loss) were treated with parenteral nutrition (52). These malnourished
patients had increased volume of distribution with gentamicin, relative to patients with-
out malnutrition, who received intravenous fluids (52). The suspected mechanism was
the expanded extracellular fluid space due to hypoalbuminemia, although total fluid
intake or output was not controlled for in this study. The clearance of gentamicin, how-
ever, was not significantly changed. The authors advised to monitor gentamicin drug
levels in critically ill patients to ensure adequate serum concentrations while avoiding
nephrotoxicity. Broad-Spectrum Antibiotics. Malnutrition has negative impact on wound
healing and resistance to infection. In a prospective, randomized clinical trial of 302 adult
surgical patients undergoing contaminated procedures, the benefit of prophylactic broad-
spectrum antibiotics (clindamycin and gentamicin just prior to, 8 h after, and 16 h
postprocedure) on wound infection was evaluated relative to nutritional status (53).
With a liberal definition of malnutrition (albumin <30 g/L, total iron-binding capacity
<220 mg/dL, or weight loss >10% of usual weight), 51.7% of patients were malnour-
ished. The malnourished patients experienced reduced wound infections in response to
antibiotic prophylaxis (19.7% with wound infection if no antibiotic prophylaxis vs 6.2%
with antibiotics, p < 0.01). This finding was associated with a significant reduction in
length of hospital stay in malnourished patients (25.0 ±15.3 without vs 19.5 ±9 d with
prophylactic antibiotics, p < 0.05). The patients who did not have malnutrition, however,
received no significant benefit in terms of wound infection or length of stay (53). This
trial underscores the morbidity and health care costs associated with malnutrition. Penicillin. Penicillin is easily absorbed, not metabolized, and renally elimi-
nated (43,54). In children with severe PEM, penicillin half-life was increased and renal
filtration reduced, compared to normal controls. Both parameters normalized after nutri-
tional rehabilitation (43,54). Sulfadiazine. Sulfadiazine is 50–55% protein bound and acetylated in the hepatic
cytosol (43,54). In six children with PEM, the rate of drug absorption was reduced, as evi-
denced by peak blood levels occurring 4–8 h later than in normally nourished controls. Free
drug was eliminated at normal rates, but acetylated drug elimination was reduced, likely
owing to limited biotransformation in the malnourished liver. In six undernourished adults
(55), sulfadiazine absorption and renal excretion were unchanged, although its metabolism
was increased and protein binding reduced (40 vs 54% in normal controls). Therapeutic
doses were achieved, however, so specific monitoring was not recommended (55). Tetracycline. Tetracycline is not biotransformed and is excreted as free drug
in the urine (56). Tetracycline pharmacokinetics in eight malnourished adults were com-
pared to those of six well-nourished controls (56). Oral drug absorption was reduced and
the elimination rate increased (56). The authors proposed reduced protein binding (albu-
min was significantly lower in the malnourished) as the most likely mechanism, and
94                                                   Part II / Influence of Nutritional Status

suggested more frequent dosing interval in order to obtain therapeutic drug concentra-
tions (56).
   The impact of dietary protein and caloric intake on the clearance of allopurinol and its
metabolite oxypurinol has been examined in a series of small cross-over studies of nor-
mally nourished men. Caloric intake had no significant impact on allopurinol or
oxypurinol clearance, with observations ranging from 2600 kcal (57), 1600 kcal (59), to
400 kcal (60). Allopurinol clearance also was not influenced by protein intake, but
oxypurinol clearance was reduced during periods of limited protein intake (57–60).
Protein intake ranged from 3 g/kg/d to 0 g/kg/d. Clearances of inulin, creatinine, and
oxypurinol were reduced on the low protein diet treatment (0.3 or 0 g/kg/d) vs higher
protein intake (1.5–3 g/kg/d). No changes in allopurinol absorption, metabolism, or
excretion were noted, but the clearance of oxypurinol was greatly reduced on the low
protein arm (58), and its half-life increased (59). Although these four studies each
involved a small number of subjects (five to seven each) and were conducted by the
same group, the consistency of the data are reassuring, and suggest increased risk of
toxicity with allopurinol use during periods of limited protein intake.
   Chloroquine pharmacokinetics were measured in eight malnourished adults with mean
albumin concentrations of 30 g/L vs seven normal controls with albumin 37 g/L (61).
Drug half-life and distribution were unchanged, but clearance was significantly increased.
Similar therapeutic concentrations were achieved, and no increased toxicity was observed,
though this trial was subject to type II statistical error.
   INH is acetylated by the liver. INH absorption was not impaired, but acetylation was
slowed in 31 children with PEM (62). The frequency of hepatotoxicity (as evidenced by
transaminitis and jaundice), in a cohort of 130 children with PEM followed for 3.5 yr, was
increased threefold relative to normally nourished controls (28). Hepatic toxicity was not
significantly impacted by acetylator status (28). In 13 South African children with tuber-
culous meningitis, baseline PEM was generally improved after 6 mo treatment with
nutritional supplementation and a four-drug regimen (20 mg/kg INH, 20 mg/kg rifampi-
cin, 30 mg/kg pyrazinamide, and 20 mg/kg ethionamide) (63). INH concentration and
systemic elimination did not change after nutritional rehabilitation, although slow, inter-
mediate, and fast acetylators were noted (63). The differences in hepatotoxicity reported
by these two studies may reflect the impact of treatment time (6 mo vs 3.5 yr) and
statistical power derived from larger subject numbers.
   In eight undernourished adults, who were free of tuberculosis, the peak plasma con-
centration, AUC, and protein binding of rifampicin were significantly reduced but the
half-life was unchanged and renal clearance increased (64). In 10 other undernourished
adults who had tuberculosis, the AUC and protein binding were reduced further, and
Chapter 5 / PCM and Drugs                                                                 95

glutamyl transferase levels elevated (64), suggesting that toxicity risk may increase with
the combination of malnutrition and disease.
   The impact of a 7-d, 1000-kcal deficit, 0.3 g protein/kg diet on pharmacokinetics of
a single intravenous dose of cimetidine was measured in a cross-over design with a group
of five normal volunteers (65). Although cimetidine renal clearance was unchanged,
fractional excretion of the drug was significantly increased, suggesting net tubular secre-
tion of the drug during the protein- and calorie-restricted diet.

    The greatest limitation in currently available data is the dearth of trials comparing the
impact of malnutrition on drug action, which leaves health care providers with limited
evidence on which to base practice decisions. Many available studies have examined
antibiotics, such as chloramphenicol and tetracycline, that are less commonly used today—
whereas a broad spectrum of newer drugs are in current use with no data on the impact of
malnutrition on their action.
    The quality of clinical trials is somewhat limited. For ethical reasons, prospective ran-
domized controlled trials of a drug vs placebo in a malnourished cohort with an indication
for the drug in question cannot be undertaken. Thus, available data are largely from case-
control or open-label observations, study designs that are prone to bias. Because both mal-
nutrition and infection can independently impact hepatic protein synthesis and fluid shifts,
a further confounder is the difficulty in independently evaluating the impact of infection
from that of malnutrition. A further difficulty is finding large enough cohorts of patients
with similar degrees of malnutrition to power a comparison of one drug to another.
    In the realities of clinical practice, malnutrition proceeds along a continuum that
begins with mild, short-term deficits and can progress to severe, protracted losses of fat,
muscle, and organ function, ending in death. The preponderance of data regarding mal-
nutrition and drugs is from these more extreme degrees of PEM. The few studies with
underweight but not wasted children and with critically ill adult patients in conditions of
severe metabolic stress, suggest that drug distribution and metabolism may be impacted
by lesser degrees of malnutrition. Thus, we have limited data on which to make decisions
about the risk and effectiveness of drug therapy, based on malnutrition.
    For clinical purposes, it would be most helpful to see future evaluation of medications
using malnutrition (and obesity) stratifications by universally accepted standards, such
as the WHO/NCHS (1) standards for children and National Heart, Lung, and Blood
Institute body mass index categories for adults (66). Clinical trials and bedside practice
will continue to use height and body weight as surrogates for the much more difficult to
obtain body composition measures of metabolically active tissue.
    Simple, inexpensive, and rapid feedback methods for monitoring drug concentrations
in the field or primary provider’s office would be very helpful in high-risk patients. Noted
96                                                           Part II / Influence of Nutritional Status

discrepancies with findings should be reported in order to encourage continued discus-
sion of the topic.

   Clinical trials with pharmacokinetic modeling of representative members of drug
classes are needed in large patient groups with varying degrees of protein and calorie
malnutrition. Trials are also needed in cases with single nutrient deficiencies, particularly
those that impact on major metabolic pathways.
   Animal experiments should be undertaken with measurement of total body water, fat
and protein compartments during PEM and various levels of obesity—to clarify some of
the difficult questions regarding drug distribution, sequestration into body compart-
ments, and protein binding. Animal models also could provide a clean experimental
evidence base for drug handling during single nutrient deficiencies.
   Because critically ill patients in current hospital practice have considerable rates of
nutritional risk at admission, and nutritional status can worsen during prolonged hospital
care, pharmacokinetics studies are indicated in patients with varied levels of metabolic
stress so that the concurrent impact of nutritional status on drug effectiveness can be
evaluated. Data on the impact of concurrent feeding with enteral or parenteral nutritional
support in patients with various levels of malnutrition and clinical stressors are sorely
lacking, and have the potential to radically change medical practice.

    First and foremost, all patients who are ill enough to require medications should be
screened for malnutrition, using standard parameters. The components of this evaluation,
as a minimum should include evaluation of body weight relative to standards, of serum
protein status, and the likelihood of nutrient deficiencies due to dietary practices. Because
all health care facilities in the United States are required to have a process in place for
nutritional screening, it may be possible to obtain a report from the facility’s systematic
evaluation of patients who are at nutritional risk.
    Second, the available research is fairly consistent at recommending the advisability of
monitoring for drugs with a narrow safety profile in high-risk patients owing to their
malnutrition. With the huge prevalence of malnutrition in various clinical states (e.g.,
cancer, HIV, geriatrics, etc.) and clinical settings (intensive care units, skilled nursing
facilities, nursing homes, chemotherapy centers), this could be an impossible task. To be
successful in this effort, inexpensive, and widely available drug-monitoring systems for
field, clinic, and even home use will need to be developed.
    Clearly, because malnutrition alone can lead to death, efforts should be maximized to
minimize time delay in using medications effectively in patients with concurrent malnu-

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Chapter 5 / PCM and Drugs                                                                                 97

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Chapter 5 / PCM and Drugs                                                                                   99

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66. viewed 8/17/02.
Chapter 6 / Influence of Obesity                                                          101

      6          Influence of Obesity
                 on Drug Disposition and Effect

                 Joseph I. Boullata

   Differences in drug responses between patients are a result of many potential sources
of variability. These may include age, gender, genetics, and disease states—both acute
and chronic. Included in the latter are states of altered nutritional status. Providing
appropriate therapeutic drug monitoring requires an understanding of the influence of
these factors on drug disposition and effect (1). In order to make better use of invaluable
medications, altered drug effect needs to be explained or, better yet, predicted prior to
use. A better understanding of the influence of obesity on drug disposition and drug effect
may lead to more measured use of medications in this group of individuals.

1.1. Definitions and Prevalence of Obesity
   Obesity is a chronic disorder with a complex pathophysiology involving genetic and
environmental factors, which ultimately impact the balance between energy intake and
expenditure, and manifests as excess body fat. It is associated with significant risk of
morbidity and mortality, as well as increased health care costs, and reduced quality of life.
Morbidity includes diabetes, which has seen a 61% increase in prevalence since the early
1990s and is expected to accelerate as the obesity epidemic continues (2). Obesity is
considered a major risk factor for coronary heart disease and the second leading cause of
preventable death in the United States after tobacco use (3,4). The risk of comorbid
disease (e.g., diabetes, heart disease, hypertension, dyslipidemia) is tied to the degree of
   Excessive body weight is best described by the body mass index (BMI)—an expres-
sion of an individual’s weight relative to height, in kilograms per meter squared (kg/m2).
Obesity, as a disorder of excess body fat (including that stored in the midsection), is best
defined in terms of the BMI and waist circumference for adults (Table 1) (5). The BMI
and waist circumference are closely linked to health risks associated with overweight
(BMI 25) and obesity (BMI 30) (6,7). Morbidity increases at a BMI of 25 or greater,
although this may vary with specific populations. The BMI has been adequately com-

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
102                                                     Part II / Influence of Nutritional Status

Table 1
NIH Classification of Overweight and Obesity in Adults
                                                      Relative Disease Risk
                                  BMI            Men—WC 40"            > 40" (102 cm)
        Class                   (kg/m2)          Women—WC 35"          > 35" (88 cm)
Normal                        18.5–24.9          —                       —
Overweight (pre-obese)         25–29.9           Increased               High
Obesity I (moderate)           30–34.9           High                    Very high
Obesity II (severe)            35–39.9           Very high               Very high
Obesity III (morbid)               40            Extremely high          Extremely high
  From ref. 5. BMI, body mass index; WC, waist circumference.

pared to direct measurements of body composition (8). Definitions of obesity used in
drug investigations often rely on an arbitrary weight cutoff relative to an idealized weight
(e.g., actual weight      120% of “ideal” weight). This can be problematic without a
standard definition, or a substantiated reference weight that could provide a more rational
basis for classifying individuals in these studies. An evaluation of various reference
weights is discussed in the next section.
    Definitions of obesity in children have been less well defined, but age and gender
cutoff values for BMI linked to adult definitions have been proposed (9). The issue in
children revolves around how much adiposity is necessary for, and at what point is it
excessive during, growth. The recent linking of percent body fat data with BMI can allow
for study of relationships between body composition and morbidity in children (10). Up
to this point, obesity has been defined somewhat arbitrarily by the percentile ranking of
BMI within the population distribution, such that a BMI between the 85th and 95th
percentiles indicates overweight, and above the 95th percentile indicates obesity (11).
    Using these definitions, the prevalence of obesity continues to climb across all age
groups. Current estimates are that 65% of American adults are overweight (34%) or obese
(31%) (12). This translates to more than 100 million adults in the United States making
it the most prevalent chronic disease. Morbid obesity (BMI 40), associated with the most
severe adverse health consequences, has nearly tripled since the 1990s (13). Both over-
weight and obesity are also highly prevalent in children and adolescents with rates con-
tinuing to rise (14). The rates of obesity are reported to be 10.4 to 15.3% in children and
15.5% in adolescents in the United States (15). The National Health and Nutrition Exami-
nation Survey (NHANES) data suggest that childhood obesity has doubled, while the rates
have tripled for adolescents in a span of 20 years (15). This trend of increasing prevalence
of obesity in adults and children is present outside the United States as well (16–18).
    Given the higher risk of morbidity in obese individuals, higher health care needs,
including the use of medications is expected. The difficulty in addressing appropriateness
of medication regimens in obese patients is in part based on limited drug-specific data and
on varying clinical approaches to describing or even recognizing obesity.

1.2. Assessing Body Weight for Drug Dosing
   Although not perfect, the most valid and practical indicator of obesity is the BMI. This
tool gained universal approval and was recommended for use in determining body habi-
Chapter 6 / Influence of Obesity                                                         103

tus and risk for morbidity and mortality a number of years ago (19,20). BMI is the best
predictor of the effect of body weight on health risks, but is not easily adapted, and
therefore has been considered of little practical use, for the dosing of medications.
Although weight-based dosing of a drug is less likely to be problematic at a BMI of less
than 30, in obesity, the use of a patient’s actual (i.e., total) body weight may be inappro-
priate and can increase the risk of adverse effects. But something as basic as which weight
should then be used for drug dosing in obese individuals has been fraught with contro-
versy. Numerous dosing terms and predictive equations have been used (Table 2). The
term dosing weight is universally acceptable whether referring to an actual total body
weight, or an alternative body weight—as one would consider in volume overloaded or
obese patients. The derivation of the best dosing weight for use in obesity is unclear.
Adjusting a body weight for dosing in obesity will depend on the substance (e.g., crea-
tinine, nutrient, drug) being evaluated or dosed and how it is handled differently, if at all
different, in obesity. Dosing may be based on the total body weight (TBW) or on the lean
body weight (LBW) or on some adjusted weight in between the other two depending on
the drug. The terms used to describe body weight in this chapter refer to their original
descriptions as summarized in Table 2 (21–25). The reader is encouraged to appreciate
the differences between the equations by calculating each body weight term using their
own data.
   The life insurance tables, from the earliest versions to those of 1983, are the source of
the terms “ideal” and “desirable” body weight. They were derived from data on low-risk,
otherwise healthy, young persons able to afford life insurance as collected beginning in
the 1930s (26–29). These data from a limited population sample describing an “ideal” or
“desirable” weight for a given height are also reflected in a simple-to-use regression
equation derived from those tables (21). The weight-for-height provided in the insurance
tables, or by the equation based on those tables, is not an “ideal” to be aimed for, is not
representative of the general population, and is not necessarily of any value to drug dosing
in obese patients. Additional predictive equations for “optimum” body weight and for
LBW have been described and continue to be widely used (22,23).
   The “optimum” weight equation was described for diabetic persons with a medium-
sized frame for use in determining an approximate caloric requirement (22). The sugges-
tion was made to increase by 10% for patients of “heavy” frame, and decrease by 10%
for those of a “light” frame. As can best be determined, this equation is empirically
derived but considered adequate for its intended purpose in clinical practice. In a case
report discussing gentamicin toxicity, the size of the daily dose as a function of body
weight was described (23). The weight used to estimate creatinine production was critical
in determining creatinine clearance and hence drug dosing. The suggestion was made to
use LBW, with obese patients requiring an adjustment in TBW to derive their lean weight,
based on an empiric equation. This equation is one of the most frequently cited for
determining a patient’s LBW despite not being based on any actual subject measurements
(21,23). The optimum and LBW values derived through these two equations have even
been improperly referred to quite often as “ideal” body weight. However, the very con-
cept of “ideal” body weight was questioned years ago in well-supported and valid cri-
tiques (20,30,31).
   Even though ideal body weight may correlate with BMI in overweight and possibly
in level I obese individuals, this has not been shown true at all levels of obesity (32). But
104                                                           Part II / Influence of Nutritional Status

Table 2
Equations for Estimating Body Weights
Body Weight Term              Equation for Men                            Equation for Women
Ideal weight           52 kg + 1.9 kg/in > 5 ft                    49 kg + 1.7 kg/in > 5 ft
Optimum weight         106 lbs + 6 lbs/in > 5 ft                   100 lbs + 5 lbs/in > 5 ft
                       [48.2 kg + 2.7 kg/in > 5 ft]                [45.5 + 2.3 kg/in > 5 ft]
Lean weight            50 kg + 2.3 kg/in > 5 ft                    45.5 kg + 2.3 kg/in > 5 ft
Body cell mass         (kg)[79.5 – (0.24)(kg) – (0.15)(y)]         (kg)[69.8 – (0.26)(kg) – (0.12)(y)]
                                    73.2                                         73.2
Lean Mass              (1.1013)(kg) – (0.01281)(BMI)(kg)           (1.07)(kg) – (0.0148)(BMI)(kg)
   From refs. 21–25.
   kg, kilogram of body weight; in, inches; ft, feet; lbs, pounds; y, years of age; BMI, body mass index in

more to the point, if the purpose is to (a) define a reference “normal” weight with which
to compare obese individuals, and to (b) derive proposed dosing adjustments for obese
subjects, then several factors beyond height and weight need to be considered. To be of
most value, a reference weight should be based on actual height/weight data from a
representative sample of the entire population, or better yet, should be based on the body
composition of a reference sample. External measures of obesity (i.e., BMI) remain more
practical than obtaining body composition data, however, the latter should be used to
better define parameters in studies of drug disposition. Body composition is likely much
more important for this purpose than height and weight alone. Age and gender influence
body composition and should be taken into account in determining “normal” expected
body weights. Age and gender influence lean tissue, which in turn influences metabolic
rate (24). Having dispensed with “ideal” weight as a reference point for patients, a focus
on lean body mass is needed.
    Equations for lean body mass and body cell mass have been described. The equations
take into account age and the greater absolute lean body mass found in obese patients
(24,25). A proportion of the sample populations used to derive these equations were in
fact obese, although the numbers of morbidly obese patients were small (33). It has been
suggested that the lean body mass equation (25) may under predict true lean body mass
of the morbidly obese subject (33). This may require revisiting the data in order to readjust
the constants (33). Regardless, this remains the only equation that takes BMI into account.
It is proposed that this equation best reflects lean body mass—until further body compo-
sition analysis yields a more accurate predictive equation or population-specific equa-
tions (34). The lean body mass from this equation should be used as the reference standard,
for the true LBW, on which to compare TBW between obese and nonobese individuals
for the purposes of understanding drug disposition. Either in its original format or the
more condensed form below (35), where TBW is the total body weight in kg and Ht is
the height in cm:
                              Men: (1.10)(TBW) – (120)(TBW/Ht)2

                            Women: (1.07)(TBW) – (148)(TBW/Ht)2
Chapter 6 / Influence of Obesity                                                         105

   It is hoped that improved equations will be developed based on more recent data from
a more diverse population coincident with body composition. This data may be available
from a broad national sample (36). Such body composition data may be helpful in address-
ing the dosing issues of obese individuals. Depending on body composition, the distribu-
tion of a drug under study can be identified and corrections to body weight can be inferred.
In this way, a dosing weight is based on the drug rather than relative to a standard weight
for height. Dosing weight correction factors have been used to adjust body weight to a
value between the TBW and LBW for dosing, although most have not been systemati-
cally studied. The general equation often used to adjust body weight is:
                           DWOB = LBW + (CF)(TBW – LBW)
where DWOB is dosing weight for obesity, LBW is the lean body weight, CF is a correc-
tion factor, and TBW is the total body weight. The LBW will vary depending on the
method used to determine it—but again the lean body mass equation is suggested (35).
After all, the distribution of body fluid is related to the lean body mass, and overall
metabolic activity is also associated with the lean body mass. If a single dosing weight
correction factor is used for all obese patients, instead of being individualized to the drug
being administered, some drugs may be significantly underdosed, whereas others may be
given in overdose. The correction factor is a fraction of the “fat” weight (i.e., beyond
LBW) that normalizes the volume of distribution in an obese patient to that in a nonobese
patient. Data is based on the excess weight beyond the predicted LBW with which a
drug’s pharmacokinetic characteristics are best correlated. This relationship is rarely, if
ever, correlated to a patient’s actual lean body mass. What was not recognized early on,
and has carried forward virtually unaddressed by continual use of ideal body weight, is
that not only is it not necessarily physiological, but excess weight is more than just
adipose tissue and the composition varies between obese subjects. Unfortunately, there
is not an abundance of body composition data. In general, nonobese, middle-aged adults
have a fat mass of about 20 kg that corresponds to about 25% of TBW in men and about
33% of TBW in women. Obese individuals have, on average, a larger lean body mass than
their nonobese peers, accounting for 20–40% (mean 29%) of the excess weight in obesity
(37). In other words, as much as 60–80% of the excess weight in obesity may be adipose
   Unfortunately, most pharmacokinetic studies in obesity make use of predictive equa-
tions without the benefit of actual body composition data. In dosing medications, most
clinicians make general assumptions for the dosing weight in obese patients focusing on
the excess fat. But it is the lean body mass that correlates well with total body water—
including the central compartment, metabolic activity, and can be correlated with drug
clearance. Clinicians need to keep in mind that obesity can influence the tissue distribu-
tion of a drug, its clearance, and its clinical effect. However, this occurs not simply
because of excess fat mass, but because of other physiological changes. This translates
into modified dosing strategies for initial and maintenance doses. This is especially
important for medications for which minimal effective concentrations or narrow thera-
peutic indices exist.
   Although from a practical standpoint medications that follow weight-based dosing in
adults warrant important consideration in obesity, understanding the broader impact of
obesity on drug disposition and effect to explain or predict drug effects in obesity is
106                                                  Part II / Influence of Nutritional Status

   A review of how obesity impacts drug absorption, distribution, metabolism, excretion,
and action should be based on the available scientific data. It is interesting to note the
discrepancy that exists across the study of obesity. Despite major improvements in the
understanding of the societal, economic, pathological, and clinical outcomes of obesity,
there remains only limited study of pharmacokinetics and pharmacodynamics in this
disorder at the current time (35). One should understand that it is not a simple task in any
human study to clinically assess pharmacokinetics and pharmacodynamics. In hepatic
drug metabolism, for example, blood flow, protein binding, and tissue binding are each
important factors that need to be taken into account and are also each difficult to assess.
Many of the assumptions made may not always be accurate for obese individuals. In fact,
persons with obesity can be considered quite a heterogeneous group. Subjects with a BMI
of 30–35 may be quite different than those with a BMI of 45 and greater. A given BMI
cannot differentiate the degree of fatness between individuals (38). Indeed, within a
group of individuals at the same BMI, there may be differences in body composition that
ultimately influence drug distribution and clearance.
   Variability in fat mass may occur with a number of factors. Fat mass increases as
individuals age. Gender is also a factor, with women having higher body fat mass than
men in general. Inactive individuals are likely to have higher fat mass than those who are
more active. Ethnicity can also be a factor with individuals of Native American, Hispanic
American, and Asian heritage more likely to have higher percent body fat than Cauca-
sians, who in turn may have higher percent body fat than Africans or Polynesians (39–42).
Percent body fat may differ between individuals of the same BMI (39,42). Even the ana-
tomic distribution of that fat, including the blood flow to those depot sites, may vary by
gender and ethnicity (43). Each of these variables will need to be accounted for in future
study of the influence of obesity on drug disposition and effect. Anatomic and physiologi-
cal changes that occur with obesity may impact on a drug’s absorption, distribution, and
elimination through metabolism or excretion.

2.1. Absorption
   Altered gastrointestinal (GI) transit time and a higher splanchnic blood flow may
modify drug absorption including a reduction in the bioavailability of drugs with high
extraction ratios. However, the limited data suggest that oral drug absorption including
drugs with higher extraction ratios may be no different in obese individuals (e.g.,
cyclosporine, dexfenfluramine, midazolam, penicillin, propranolol) (44–47). Absorp-
tion from transdermal or subcutaneous administration is not well characterized in obe-
sity. Intramuscular injection in many cases may be better characterized as intralipomatous,
which has not been well studied either.

2.2. Distribution
   The distribution of a drug throughout the body following absorption is determined by
several factors—some related to the drug (e.g., lipophilicity, degree of ionization), others
related to the body (e.g., blood flow, tissue-binding sites). Plasma-protein binding, body
composition, tissue size, tissue permeability, and drug affinity for various tissues each
determine a drug’s distribution. Knowledge of body composition, regional blood flow,
and plasma-protein binding is necessary.
Chapter 6 / Influence of Obesity                                                         107

   Obese subjects have a larger fat mass and a larger lean body mass in absolute terms
compared to nonobese individuals of the same age, height, and gender. In relative
terms, lean tissue as a percent of TBW is reduced, whereas percent adipose tissue
mass is increased. In other words, not all the excess weight in obesity is made up of fat
relative to the nonobese individual. The extra lean tissue makes up about 20–40% of the
excess weight, about 29% on average across a BMI range of 29–47 (37). This increase
in lean body mass does not hold for patients with obesity associated with Prader-Willi
syndrome or Cushing’s syndrome (37). Weight-based drug dosing would need to take
into account the relative distribution into various tissue compartments. Total body water
in obesity was estimated to include approx 30% water content in excess tissue (48).
Although lean body mass may be determined through bioelectrical impedance analysis
or whole body densitometry, neither of these is yet clinically practical across all settings.
An equation that at least takes gender, weight/height, and BMI into account allows an
estimate of lean body mass (see Subheading 1.2.).
   There are increases in blood volume, cardiac output, and organ mass in obesity that
also can influence drug distribution. The proportion of cardiac output that reaches the
adipose tissue is relatively small (~5%) compared with the blood flow to lean tissue and
viscera, and might be reduced further with increasing degrees of obesity (49,50). Adipose
blood flow may actually be less in morbidly obese individuals compared to the moder-
ately obese or thin (51).
   Drugs can bind to several circulating proteins—albumin, 1-acid glycoprotein, and
the lipoproteins. Albumin concentrations do not appear to be altered as a result of “mod-
erate” obesity, whereas 1-acid glycoprotein levels are increased (52). This suggests an
inconsistent alteration in drug affinity in obese individuals. The effect that obesity has is
more likely on 1-acid glycoprotein than on albumin, thereby decreasing the unbound
fraction of basic drugs in some but not all instances (52–54). Drugs bound to 1-acid
glycoprotein may exhibit lower free drug concentrations (e.g., propranolol), or no change
in free drug levels (e.g., triazolam, verapamil), whereas the free level of drugs bound to
albumin do not appear to change (e.g., phenytoin, thiopental). Despite little difference in
serum albumin concentrations in obese individuals, there may be increased binding of
fatty acids to the albumin molecule, thereby potentially altering drug-binding sites. The
clinical significance of any changes is unclear. The associated tissue binding that may
determine the clinical relevance of alterations in unbound plasma drug concentration is
not known. There are a balance of drug affinities between tissue components and plasma
proteins that ultimately determine clinical significance. Alterations in the concentration
of, or affinity for, plasma proteins may influence drug availability to the tissues where it
may be active or may instead be cleared. It may come down to the competition between
a drug’s binding characteristics in vivo between lean tissue, transport proteins, and adi-
pose tissue. Lipoprotein levels can also be elevated in obese individuals potentially
impacting on pharmacokinetics and effect (e.g., cyclosporine) (55,56). The potentially
altered tissue perfusion and tissue binding has not been well studied in obesity.
108                                                    Part II / Influence of Nutritional Status

   It may be expected based on body composition that lipophilic drugs have a larger
volume of distribution in obese patients. Although this is sometimes the case (e.g.,
bisoprolol, diazepam, thiopental), it is not always so (e.g., cyclosporine, digoxin,
procainamide). Hydrophilic drugs may actually have a larger volume of distribution
(e.g., aminoglycosides, ampicillin, cefamandole, cefotaxime, ciprofloxacin, nafcillin) or
a similar volume of distribution (e.g., cimetidine, ranitidine) in obese patients. A point
to remember is that a drug’s lipophilicity, based on its oil-to-water partition coefficient,
is only one of several characteristics of a drug and unlikely to be the driving factor to
overcome other factors (e.g., blood flow, in vivo binding competition) in determining
drug distribution on its own (57,58). Lipophilic agents do not necessarily have larger
distribution volumes in obese individuals and some may not even be stored in adipose
tissue (59). Distribution of a hydrophilic drug into adipose tissue or into the excess lean
tissue that supports the excess fat mass may need to be taken into account for dosing. Most
hydrophilic drugs distribute to a limited degree into excess adipose tissue, but may
distribute into excess lean tissue. Besides increases in fat and lean body mass, obesity is
associated with increases in organ mass, cardiac size and output, blood volume, and
regional flow. Even polar compounds may not behave similarly with regard to volume
of distribution and body weight (58). Antipyrine distributes into body water and exhibits
a slightly higher absolute volume of distribution in obese subjects (predicted by a higher
absolute body water in obese subjects), but significantly reduced volume of distribution
when corrected for TBW (predicted by a lower relative body water) (32). This important
point suggests that comparisons of drug distribution between obese and nonobese indi-
viduals should be done on the basis of TBW. That is, the volume normalized to TBW
rather than the absolute volume of distribution. A decreased volume of distribution when
normalized to TBW indicates a drug that distributes less into the excess adipose tissue.
This indicates that antipyrine distributes into the excess body weight above the estimated
LBW by a factor of 30%, which incidentally correlates with estimates of excess lean

2.3. Elimination
   The elements that determine elimination of a drug, whether through metabolism or
excretion, may be altered in obese individuals. Increased cardiac output, fatty infiltration
of the liver, portal inflammation and fibrosis, increased renal plasma and creatinine
clearance are all known to occur in obesity (60–62).
2.3.1. HEPATIC
   The fatty infiltration of the liver could affect hepatic metabolic activity. Fatty infiltra-
tion of the liver is more severe with increasing BMI, and may impact on the organ’s
metabolic activity. Using antipyrine as a marker of hepatic oxidative enzyme function,
drug half-life was increased in obese individuals compared to lean volunteers (63).
However, this was because of an increased apparent volume of distribution, although no
change in drug clearance was observed (63). The volume of distribution for antipyrine
corrected for TBW is significantly reduced in obese patients given distribution limited
to lean tissue (described in Subheading 2.2.4.) (63). Given the multiple pathways by
which antipyrine can be metabolized, it is not clear whether there is actually no change
Chapter 6 / Influence of Obesity                                                            109

in activity of any specific pathway, or whether the measured effect is the resultant net
effect across pathways—some increased, others decreased. Drugs that undergo signifi-
cant first-pass hepatic extraction appear to have similar rates of clearance in obese com-
pared to nonobese individuals indicating that hepatic extraction is not dependent on body
weight. Some, but not all, drugs that undergo hepatic oxidation and conjugation may have
increased clearance in obesity.
   Hepatic drug clearance through phase I reactions may be increased (e.g., predniso-
lone), decreased (e.g., methylprednisolone, triazolam), or unchanged in obesity. This
variability may be explained by specific enzyme activity. For example, the activity of
CYP2E1 may be increased (e.g., chlorzoxazone), whereas CYP3A activity may be
reduced or unchanged (e.g., erythromycin, cortisol) as body mass increases in obesity
(64–67). Markers for specific CYP3A isoenzymes will be necessary to differentiate the
impact of obesity on each of them. Based on caffeine as a marker of CYP1A2, there appears
to be no difference in activity of this isoenzyme between obese and nonobese individuals
(63). All told, there remains very little isoenzyme-specific data. Some phase II reac-
tions may be altered. The activity of both glucuronide and sulfate conjugation appear
to increase in obese individuals and may impact on drug clearance (e.g., lorazepam,
oxazepam) (69,70). On the other hand, activity of glycine conjugation or of acetylation
does not appear to be altered by obesity (71,72). Adipose tissue itself possesses metabolic
capacity that may be increased based on the larger fat mass. Although the findings of
altered metabolic enzymes from animal models of obesity are many, the extrapolation of
each unique model (e.g., overfeeding versus genetic defect) to the human condition is
considered poor (73,74).
2.3.2. RENAL
   Although using actual body weight may overestimate creatinine clearance predic-
tions, and the empirically derived LBW underestimates it, a 30% adjustment appears to
be the best predictor, although requiring prospective confirmation (75). This reflects the
more metabolically active lean tissue, the source of creatinine, rather than renal capacity.
Generally, renal drug clearance can be increased in obesity (e.g., aminoglycosides,
cefamandole, cefotaxime, cimetidine, ciprofloxacin, lithium, procainamide). This is
partly a result of increased glomerular filtration, whereas indirect evidence suggests that
tubular secretion is also increased thereby further affecting renal drug clearance in obe-
sity (72,76–78). Increased drug clearance is the result of increased tubular secretion (e.g.,
cimetidine, ciprofloxain, procainamide) and reduced tubular reabsorption (e.g., lithium).
Increases in glomerular filtration as measured by creatinine clearance can be increased
in obese individuals (62,79,80) but have also been reported to be unchanged in some
obese patients (76,81). The reasons for this discrepancy are not clear but may relate to
variability in body composition (i.e., actual lean body mass) and in renal dysfunction
among the various obese subjects and patients.

2.4. Drug Effect
   Even if, after taking any pharmacokinetic changes into account, a normal drug concen-
tration is achieved and delivered to the site of action in an obese patient, the clinical effect
of the drug may still be other than expected. This may occur with alterations in target-
tissue sensitivity, whether at the level of the drug target or a downstream effect. There
110                                                  Part II / Influence of Nutritional Status

may be increased sensitivity to some drugs (e.g., glipizide, glyburide, prednisolone,
triazolam) (54) and decreased sensitivity to others (e.g., atracurium, verapamil) (82).
Receptor expression or affinity may be altered. The drug effect may be more pronounced,
including toxic effect, as an extension of pharmackokinetic variables or pharmacody-
namics, but is poorly predictable (83). Given the wide number of genes and loci impli-
cated in obesity (84), whether owing to mutations, phenotypic associations or linkages,
the possibility exists for associations or overlap with genetic markers of drug metabolism
or drug response.

2.5. Integrating the Data/Approach
   Loading doses of a drug will be based on information about a drug’s volume of
distribution as it relates to TBW (L/kg) (or body composition when possible). On the
other hand, maintenance doses will be based on the total clearance of the drug from the
body (L/h) as documented in obese subjects or patients. When volume of distribution is
normalized to TBW the extent of drug distribution into the excess weight, which is of
mixed composition, beyond the LBW, has given rise to the figures (correction factors)
used to adjust the body weight. This, however, assumes that the subject’s LBW is cor-
rectly estimated, and that excess tissue is adipose alone. This being the case, there should
be no significant difference in values between men and women. However, the degree of
distribution into the excess weight above the predicted ideal or lean weight, is reported
to differ for the hydrophilic analgesic acetaminophen with men having an apparently
higher distribution into the excess tissue (85). This would be accounted for by the higher
proportion of lean tissue in men, including more lean tissue in the excess weight above
the predicted lean weight.
   Therefore, the ratio of TBW-normalized volume of distribution in obese subjects to
that in nonobese subjects can help guide which body weight should be used for weight-
based loading doses:
           VD/kg TBWOB : VD/kg TBWNon-OB                   Dosing Weight
                        1                               Actual TBW
                     0.7 up to 1                        An adjusted body weight
                     <0.7                               LBW

  For example, the volume of distribution for vecuronium is about 0.5 L/kg TBW in
obese patients and about 1 L/kg TBW in nonobese individuals. The ratio of the value in
obesity to the value in controls is 0.5 (0.5 1), suggesting the use of LBW for the loading
dose of this drug. And a similar approach using total body clearance may be possible in
guiding which body weight should be used for weight-based maintenance doses in drugs
whose activity throughout the dosing interval is concentration dependent:
                   ClT OB : ClT Non-OB                  Dosing Weight
                              1                        Actual TBW
                           <1                          Adjusted or LBW

   For example, the clearance for vecuronium is about 16 L/h in obese patients and about
20 L/h in nonobese individuals. The ratio of the value in obesity to the value in controls
is about 0.8 (16 20), suggesting the use of adjusted or LBW for the maintenance dose
Chapter 6 / Influence of Obesity                                                          111

of this drug. Of course, data from well-designed studies examining drug-specific volume
of distribution and clearance, as well as drug effect between obese and nonobese indi-
viduals will provide the best guidance compared to the empiric advice presented here.

    This section provides an overview of some of the drug-specific data available in the
literature to help guide decision making in the pharmacotherapy of patients with obesity.

3.1. Anticonvulsants
   The dosing of phenytoin can be complex enough in patients with a healthy BMI given
the many factors that can impact on its disposition. In obesity, the volume of phenytoin’s
distribution is increased both in absolute terms and when normalized to TBW (86). This
indicates that the drug distributes especially into the excess adipose tissue of obese
individuals. The significant distribution of phenytoin into adipose tissue sets the stage
for potential redistribution from this site (87). The data suggest that a loading dose for
phenytoin should be based on an adjusted body weight using a correction factor of greater
than 1, in other words dosing based on at least TBW. At the same time, the metabolic
clearance of phenytoin appears to be increased in obesity (86). This does have the poten-
tial to decrease following successful weight loss (88). Conversely, obese individuals
have a slightly reduced clearance of carbamazepine, which increases following reduction
in body weight associated with increased physical activity (89). Whether the increased
clearance results from weight loss itself, a decrease in hepatic fat, or the effect of dietary
changes on drug clearance is unclear. Along with a lower clearance, the volume of
distribution of carbamazepine is lower in obese individuals when normalized to actual
body weight, despite a higher absolute volume of distribution (89,90). This suggests that
an adjusted body weight may be used for initial dosing of carbamazepine in an obese
patient, but that maintenance doses could be administered at longer intervals. Doses of
phenobarbital should be based on TBW in order to achieve therapeutic concentrations in
obesity (91).

3.2. Antimicrobials
   Dosing adjustments of antimicrobials as a class are rarely made based on body weight
or degree of obesity, but are based instead on drug-specific data. This drug-specific
information will determine whether adjustments should be made, or whether dosing
should take actual, lean, or an adjusted body weight into account. A number of findings
on the dosing of antimicrobials in obesity have been recently reviewed (35,92). Much is
based on the degree of drug distribution into lean and fat mass, and on the influence of
obesity on drug clearance. Some studies have sought to optimize doses of moderately
lipophilic antimicrobials in obese patients (35). Based on a summary of the literature,
recommendations for dosing have been provided. These recommendations include drug-
specific correction factors for antimicrobials requiring dose adjustment in obesity (35,92).
   For -lactam drugs, a correction factor of 0.3 is suggested for use in the dosing weight
equation—although no clinical study data exist to support this. Using patients as their
own control before and after intestinal bypass-associated weight loss, the volume of
distribution for ampicillin decreased from 0.6 L/kg to 0.41 L/kg, indicating some distri-
112                                                  Part II / Influence of Nutritional Status

bution into adipose tissue for this hydrophilic compound (93). Although the absolute
volume of distribution is increased for nafcillin, no significant difference is seen in the
TBW-normalized volume of distribution or in total clearance in a morbidly obese patient
(94). This would imply the potential to dose nafcillin based on actual body weight, and
the authors suggest dosing modification upward to 3 g q6h in obesity (94). An area of
concern is the preoperative dosing of antimicrobials to prevent postoperative infection
in obese patients undergoing surgical procedures. A 1 g dose of cefazolin as antibiotic
prophylaxis for surgery in patients with BMI greater than 40 resulted in serum concentra-
tions below the minimal inhibitory concentration for several organisms (95). An adjustment
to 2 g cefazolin reduced surgical site infection rates from 16.5 to 5.6%, p < 0.03 (95).
Cephalosporin clearance may also be increased in obesity, requiring repeated dosing
during an operation that lasts longer than 2–3 h (96).
    The aminoglycosides are quite similar to each other from a physicochemical stand-
point, exhibiting comparable pharmacokinetic properties. This includes volumes of
distribution that approximate the extracellular fluid volume. Obese individuals would
be expected to exhibit increased absolute volumes of distribution given the increase in
total body water, but lower values when adjusted for TBW. The typical weight-based
dosing of aminoglycosides takes renal function into account in determining a dosing
interval. Dosing aminoglycosides in obese patients using actual body weight can result
in higher than expected serum concentrations, whereas LBW may result in subtherapeutic
levels. A suitable correction factor for establishing a dosing weight that lies between lean
and actual weights varies with the study and may differ with degree of obesity, and
presence of infection. A well-recognized method for predicting gentamicin parameters
is to use an adjusted dosing weight that incorporates only 40% of the excess weight—
that is, a correction factor of 0.4 in the dosing-weight equation (81). This would provide
the basis for an initial dose of aminoglycoside. Given the variability in correction factors
determined for aminoglycoside dosing in obesity (97), it has been suggested that serum
concentrations still be used to monitor the patients (92). Aminoglycoside clearance is
increased in obesity (98–100). Renal clearance of aminoglycosides may be increased in
obesity, but this may be balanced out with the increased volume of distribution, so that
if an adequate dose is administered, no change in dosing interval is necessary. Larger
doses of isepamicin are required in obese, as compared to lean, intensive care unit
patients to achieve similar serum concentrations (101). This is despite a slightly lower
volume of distribution normalized to TBW, indicating some distribution into the excess
adipose tissue.
    Following single dose administration of vancomycin, volume of distribution was
higher in morbidly obese patients compared to nonobese individuals (102). The TBW-
adjusted volume of distribution was lower in obese patients compared to control subjects.
Clearance of vancomycin may be increased in obesity, but may be less pronounced at
higher BMI (79,80,102). However, the difference in clearance disappeared when normal-
ized to TBW, suggesting that the actual TBW should be used for dosing vancomycin in
obese individuals (102–104). A recent case report of a patient with a BMI greater than
100 suggests that the TBW-adjusted volume of distribution was only slightly lower, and
the clearance was only modestly elevated compared to values in nonobese patients (105).
This again confirms that TBW can be used for dosing vancomycin. Monitoring of serum
trough concentrations may help reduce the fear of using such large doses in the face of
Chapter 6 / Influence of Obesity                                                        113

the variable effect on clearance, and could identify patients who may require more fre-
quent dosing.
   The increased absolute volume for distribution for ciprofloxacin in obese individuals
becomes slightly below that of controls, proportional to BMI, when normalized to actual
body weight (76). This indicates that ciprofloxacin distributes less into the excess adipose
tissue than into the fat-free tissue. It has been estimated to distribute into about 45% of
the excess body weight (i.e., a correction factor of 0.45) (76). Drug clearance, including
renal clearance, is also increased in obese individuals (76). Given both the reduced
weight-adjusted volume of distribution and the increased drug clearance for ciprofloxacin
in obesity, dosing can be based on an adjusted weight using a correction factor of 0.45,
which can provide serum levels within the recommended range (106). Trovafloxacin
pharmacokinetics following a single dose in morbidly obese patients appear similar to
nonobese individuals with similar subcutaneous and deep adipose tissue drug concentra-
tions (107).
   Pharmacokinetic parameters for antifungal agents in obese patients have not been
evaluated. Amphotericin has been dosed based on TBW given the much greater volume
of distribution for this drug in obesity (108). No clear data exist for dosing of the azoles
in obese patients, although it has been suggested that volume of distribution and clearance
of fluconazole is greater in obesity (109). A higher dose of fluconazole is recommended
for obese patients based on the higher drug clearance observed in an obese patient com-
pared to data in nonobese patients (110). Flucytosine dosing has been based on an esti-
mated LBW in an obese patient that yielded acceptable serum drug concentration (108).
This seems rational given the lower volume of distribution normalized to TBW and the
reduced clearance identified. In that patient case, amphotericin was also used, with main-
tenance doses based on actual body weight.
   The limited data available for sulfonamides and macrolides does not establish which
weight can be used for dosing in obesity, or whether dosing should be different in obese
patients. It has been suggested that antimycobacterial agents be dosed according to LBW,
based on a single case report (111).

3.3. Chemotherapy
   Given that many chemotherapeutic agents are hydrophilic and expected to distribute
poorly into adipose tissue, dosing recommendations in obese patients could be based on
an adjusted or an estimated LBW. To limit the interpatient variability associated with the
often narrow therapeutic indices of many chemotherapeutic agents, body surface area is
often used instead to guide dosing. However, in obese patients use of the body surface
area that incorporates TBW, or the Calvert equation that incorporates the Cockroft-Gault
equation, to dose chemotherapy may result in increased drug exposure with the subse-
quent risk of treatment toxicity (112). Unfortunately, not much data exist to guide dosing.
Ifosfamide may distribute into adipose tissue more than expected, as described by a larger
volume of distribution and longer elimination half-life, which may impact on potential
for toxicity (113). Exposure of doxorubicin may also be greater in obese patients com-
pared to nonobese patients, in this case based on decreased drug clearance without a
change in volume of distribution (114). Another drug with reduced clearance described
for obese patients is cyclophosphamide (115). The apparent clearance of busulfan was
114                                                  Part II / Influence of Nutritional Status

higher in obese patients than nonobese, but an adjusted body weight using a correction
factor of 0.25 eliminates any difference, and is therefore suggested for dosing this agent
(116). For the renally eliminated drug carboplatin, using an adjusted body weight based
on a correction factor of about 0.5 provided the best prediction of drug clearance in obese
patients (117). A typical dosing approach resulted in excessive exposures (based on area
under the concentration-time curves) to 4-hydroxy-cyclophosphamide, tepa, and
carboplatin in a morbidly obese patient (112). It is suggested that an adjusted body weight
be used for dosing cyclophosphamide, thiotepa, and carboplatin, with consideration to
obtaining drug concentrations. There was a reduced weight-adjusted volume of distribu-
tion for all three agents, a slight increase in clearance for cyclophosphamide and thiotepa,
but a slightly reduced clearance of carboplatin (112).

3.4. Immunosuppressants
   Volume of distribution corrected to TBW is lower in obese individuals for both pred-
nisolone and methylprednisolone without apparent changes in plasma-protein binding to
albumin or transcortin (118,119). However, the clearance of prednisolone is increased in
obesity and correlates with TBW (118). Although there may be increased clearance of
prednisolone in obese patients, the increase in sensitivity to the drug means no dose
change is warranted. TBW is used to dose this drug. Conversely, there is a significant
reduction in clearance of methylprednisolone with obesity, such that reduced dosing
frequency may be needed, and LBW is used (119). Infusion of cortisol in obese patients
who had undergone study of fat area allowed recognition that drug clearance (absolute
and body weight-corrected) was much higher in those with larger intra-abdominal fat
areas (120). Cyclosporine may accumulate in adipose tissue, but its pharmacokinetic
parameters do not change significantly in obese patients other than a reduced volume of
distribution per kilogram of TBW (46,121). This suggests that cyclosporine dosing should
be based on LBW in obese individuals (46,122).

3.5. Neuromuscular Blockers
   Vecuronium distributes into lean tissue even in obese patients as indicated by the
reduced volume of distribution per kilogram of TBW (123). As a result, dosing of this
neuromuscular blocking agent should be based on LBW, particularly because prolonga-
tion of drug effect has been reported in obese patients (123). Recommendations have been
made to dose rocuronium on LBW also, based on findings of a lower volume of distri-
bution and clearance in patients with a higher BMI (124,125). Although time to onset of
rocuronium was slightly shorter in obese women, duration of effect and spontaneous
recovery time were no different between obese and normal weight groups (126). Neither
the volume of distribution per kilogram TBW nor total drug clearance differed between
groups, although patients were not morbidly obese, indicating that 0.6 mg/kg TBW
could be used. Although the absolute volume of distribution for atracurium is unchanged
in obesity, it is decreased significantly when normalized to total weight (82). This indi-
cates that dosing should be based on LBW. A possible alteration in protein binding and/
or desensitization of acetylcholine receptors may account for the reduced sensitivity of
obese patients to atracurium (82). Doses may need to be adjusted upward based on
hyposensitivity in these patients.
Chapter 6 / Influence of Obesity                                                       115

3.6. Sedatives, Anesthetics, and Analgesics
    Although benzodiazepines as a class are considered highly lipophilic, the impact of
obesity on the apparent volume of distribution varies with the specific agent. This does
not appear to be an effect of plasma-protein binding, which remains no different between
obese and control subjects. It was often considered that a correlation existed between the
coefficient of distribution into octanol:water and distribution into adipose tissue. Diaz-
epam, with the highest octanol:water partition coefficient, as well as midazolam with one
of the lowest coefficients each have a significantly higher TBW-adjusted volume of
distribution in obese individuals compared to controls, indicating distribution into excess
adipose tissue. On the other hand, lorazepam and oxazepam with intermediate partition
coefficients exhibit no difference in volumes of distribution adjusted to TBW between
obese and control subjects (32). The clearance of benzodiazepines appears to be increased
in obese individuals (32). The clearance of lorazepam and oxazepam increase in obese
individuals and appear to be correlated with TBW (70). This is documented for diazepam,
nitrazepam, and lorazepam, which undergo oxidation, nitroreduction, and glu-
curonidation, respectively. Furthermore, obese subjects are more sensitive to the same
dose of triazolam than are nonobese individuals (54).
    The very lipophilic agent propofol would be expected to distribute predominantly in
to adipose tissue. However, both the absolute and corrected volume of distribution are not
significantly different between obese and nonobese individuals (127). This may be
accounted for in part by the high hepatic clearance, which appears to be related to TBW.
This, in turn, suggests that propofol maintenance dosing in obese individuals should be
based on actual body weight. Thiopental, despite being highly lipophilic, may need to be
dosed lower in obese patients undergoing anesthesia, not because of volume of distribu-
tion, which is clearly larger in these patients even when adjusted to TBW, but because
of increased drug sensitivity (128,129). The volatile anesthetics halothane and enflurane
are metabolized through the liver to a greater extent in obese patients as determined by
levels of toxic metabolites, while having prolonged release of metabolites from adipose
tissue (130,131).
    The synthetic opioid analgesics are also lipophilic compounds. Sufentanil has an
elevated volume of distribution per kilogram of actual body weight but a clearance not
much different in the obese compared to nonobese individual (132). This suggests that
TBW could be used for dosing sufentanil in obesity, with a reduced maintenance dose
based on clinical effect relative to drug redistribution. However, remifentanil has a sig-
nificantly lower normalized volume of distribution and clearance in obese patients sug-
gesting that LBW would be more appropriate for dosing, and that TBW-based dosing
would result in excessively high drug concentrations (133,134).
    The over-the-counter analgesic acetaminophen is a hydrophilic molecule with an
expected lower volume of distribution, adjusted to TBW, in obese subjects (69). Clear-
ance of acetaminophen is increased in obesity, which may necessitate more frequent
dosing. So, initial dosing of this drug would not have to be increased in obese patients,
but could be adjusted. The volume of distribution for ibuprofen, once corrected to TBW,
is reduced in obese subjects relative to controls and not accounted for by plasma-protein
binding, which remains unchanged (135). Ibuprofen clearance is increased significantly
in the obese subjects and correlates with TBW.
116                                                  Part II / Influence of Nutritional Status

3.7. Other
   Limited data exist for most other drugs, including those used in cardiovascular, pul-
monary, and GI illness. Verapamil tends to have a larger volume of distribution in obese
patients, but not different than normal weight patients when adjusted to TBW, and clear-
ance is not altered (136,137). Additionally, obese patients may require higher drug con-
centrations to achieve similar cardiac effects as that in control patients (137). The
distribution volume and the clearance of digoxin appear unaffected by obesity based on
single dose studies (138,139). This follows from the limited distribution of the drug into
adipose tissue, and allows for the continued recommendation to administer digoxin based
on LBW. Lidocaine distribution normalized to TBW reveals similar values for obese and
control subjects, and should therefore be dosed based on TBW (140).
   Low molecular weight heparin (LMWH) dose and volume of distribution determine the
peak drug level, which in turn has been associated with the bleeding risk. Because the
volume of distribution for LMWHs is expected to be similar to plasma volume, dosing per
kilogram is not expected to differ between obese and nonobese individuals. Only limited
study exists thus far in obese patients. Based on a preliminary report, dalteparin doses
should make use of TBW (141). No apparent difference exists between obese and nonobese
individuals in volume of distribution normalized to TBW or in drug clearance. Unfortu-
nately, the effects of obesity on the absorption characteristics have not been examined.
Tinzaparin pharmacodynamics are not influenced across body weights of up to 165 kg
(BMI 61) when dosed at 75 and 175 units/kg of TBW (142). The pharmacodynamic
effect of enoxaparin does not seem to differ between obese and nonobese subjects (143).
   Theophylline, although considered a polar compound, is more lipophilic than caffeine
but does not correlate perfectly well with either LBW or TBW. Theophylline salts dis-
tribute predominantly into lean tissue even in obese individuals, indicating that loading
doses should be based on a LBW (144,145). As clearance may be increased in obesity,
a close monitoring program should be in place to adjust dosing, particularly if weight loss
occurs. Histamine-2 receptor antagonists, as expected by their hydrophilic nature, have
a much smaller volume of distribution normalized to TBW, but may have an increased
clearance (77,146). Clearance may be increased in obesity, in part because of active
tubular secretion of the drugs.
   A mood-stabilizing drug such as lithium, with a narrow therapeutic index, would be
important to evaluate in obesity. Lithium’s volume of distribution normalized to actual
body weight is considerably smaller in obese individuals, which is in line with the fact
that it distributes to lean tissue (78). The clearance of lithium is, however, increased in
obesity (78). From these findings, it would follow that initial dosing should be based on
LBW, and that maintenance doses should be larger to maintain therapeutic levels.
Trazodone is another mood-stabilizing agent but with considerable distribution into
adipose tissue based on an increased volume of distribution even when corrected to
TBW (147).
3.8. Obesity Treatments
   Drugs used to manage obesity have been studied as well. Presumably, appetite
suppressants would only be used when indicated and the issue of alterations relative to
control individuals would not be relevant. Although no longer on the U.S. market,
Chapter 6 / Influence of Obesity                                                        117

dexfenfluramine was found to distribute proportionally into both the excess fat and lean
tissue, despite being considered lipophilic (47). It appears from limited data that
sibutramine pharmacokinetics are unchanged in obese individuals compared to nonobese
subjects (148). In an open-label study, adolescents receiving orlistat therapy to manage
obesity also received a multivitamin supplement that included lipid-soluble vitamins
(149). Nevertheless, serum concentrations of vitamin K and vitamin D were reduced, the
latter significantly enough to warrant a recommendation for regular monitoring despite
prophylactic supplementation. Given the reduction in fat absorption induced by orlistat,
several lipophilic drugs have been evaluated in single dose studies during the course of
an orlistat regimen in nonobese subjects (150). Absorption of amiodarone was reduced
by 27%, however, orlistat had no significant effect on the pharmacokinetics of fluoxetine
or simvastatin.
   Given the anticipated surge in the incidence of type 2 diabetes among obese individu-
als in the coming years, it would be wise to study the use of hypoglycemic agents in this
population. The oral clearance and distribution volume of glyburide and glipizide do not
appear to be significantly different between obese and nonobese diabetic patients, al-
though some interindividual variability was noted and volume of distribution normalized
to TBW was lower for glyburide in obese patients (151,152). Obese patients also appear
to be more sensitive to the effects of glyburide requiring lower daily doses to maintain
therapeutic effect (152).
   Obese patients may also have cardiovascular disorders requiring drug therapy. -Adr-
energic receptor antagonists, -blockers, have been studied in obesity with particular atten-
tion given to the degree of lipophilicity amongst agents in this class. Although propranolol
is more lipophilic than bisoprolol, the corrected volume of distribution of each drug is
reduced in obese subjects consistent with distribution into excess lean tissue rather than
excess adipose tissue (53,153,154). There are also no apparent differences between obese
and nonobese in volume of distribution or clearance for sotalol, a much less lipophilic
  -blocker than propranolol or bisoprolol (155). Generally, these agents have a slightly
reduced volume of distribution per kilogram of body weight in obese subjects than in
controls regardless of degree of lipophilicity not explained by hemodynamic effects or
protein binding but likely correlated with the distribution coefficient of each at physi-
ologic pH (35).
   Turning briefly to bariatric surgery, which has helped certain morbidly obese patients
who are willing to commit to the necessary restrictions, reduce their body mass and,
potentially, some comorbid risks as well. The most common surgical approaches include
gastric restriction, gastric bypass, or intestinal bypass (156). Aside from the very real
perioperative risks and the GI complications associated with this disfiguring of the GI
tract, comes the alteration of nutrient and drug disposition. The malabsorption of nutri-
ents is expected and has been documented for calcium, magnesium, iron, group B vita-
mins including cobalamin, vitamin D, and other fat-soluble vitamins. Based on the
alteration in those portions of the GI tract normally responsible for preparing orally
administered drugs for absorption, these procedures would be expected to alter drug
absorption either by reducing time for disintegration and dissolution, or reducing the
surface area and sites for absorption (157). The data is extremely limited at the present
118                                                        Part II / Influence of Nutritional Status

         Table 3
         Values in Obesity for Volume of Distribution and Clearance of Select Drugs
                                           VD                     Cl
            Medication              (L)         (L/kg TBW)       (L/h)     Reference
         Acetaminophen               109            0.81          29           69
         Amikacin                    26.5           0.18          9.5          99
         Atracurium                  8.6            0.07          26.6         82
         Bisoprolol                  182            2             14.8         153
         Carbamazepine               98.4           0.87          1.19         89
         Ciprofloxacin               269            2.46          53.8         76
         Cyclosporine                230            2.5           42           46
         Diazepam                    292            2.81          2.3          85
         Digoxin                     981            10.7          19.7         139
         Doxorubicin                 1119           14            53.5         160
         Gentamicin                  23.5           0.17          8.5          99
         Glyburide                   47             0.44          3.2          151
         Glipizide                   19.5           0.2           2.3          152
         Labetalol                   368            3.8           90           153
         Lorazepam                   131            1.25          6.1          85
         Methylprednisolone          104            0.9           21.3         119
         Midazolam                   311            2.66          28.3         44
         Oxazepam                    97             0.84          9.4          70
         Phenytoin                   82.2           0.68          3.5          86
         Prednisolone                44.1           0.3           11.1         118
         Propofol                    17.9           1.8           1.46         127
         Propranolol                 230.5          2.7           44.3         155
         Ranitidine                  86             0.8           34.5         146
         Sotalol                     80             0.9           9.4          155
         Sufentanil                  547            5.8           1.25         132
         Theophylline                40.5           0.4           3.3          144
         Tobramycin                  19.2           0.23          7.5          161
         Trazodone                   162            1.4           8.7          147
         Vancomycin                  43             0.26          11.3         102
                                     52             0.32          11.8         80
         Vecuronium                  44.7           0.47          15.6         123
         Verapamil                   858            7             59.6         136
            VD, volume of distribution; L, liters; L/kg TBW, liters per kilogram of total body
         weight; Cl, clearance; L/h, liters per hour.

time—for example, based on serum drug concentrations, the absorption of oral penicillin
is apparently not altered following gastroplasty for morbid obesity (158).

    Although reference to altered drug disposition in obese individuals can be found in the
literature across a number of years, there has been little concerted effort to study this and
to provide clinical recommendations. There is clearly a paucity of data when it comes to
Chapter 6 / Influence of Obesity                                                               119

      Table 4
      Suggested Dosing Weight for Use in Obesity
       Medication                            Dosing Weight in Obesity
        Example                       Loading Dose             Maintenance Dose
      Aminoglycosides             Adjusted body weighta           Adjusted body weight,a
                                                                  or by therapeutic response
      Amphotericin                Total body weight               Total body weight
      Atracurium                  Lean body weight                Total body weight
      Carbamazepine               Total or adjusted               Lean body weight
      Ciprofloxacin               Adjusted body weighta           Adjusted body weighta
      Cyclosporine                Lean body weight                Lean body weight
      Flucytosine                 Lean body weight                Lean body weight
      Lithium                     Lean body weight                Larger than nonobese
      Phenytoin                   Adjusted body weighta           Adjusted body weighta
      Propofol                    Total body weight               Total body weight
      Theophylline                Lean body weight                Adjusted body weighta
      Vancomycin                  Total body weight               Total body weight
      Vecuronium                  Lean body weight                Lean body weight
      Verapamil                   Total body weight               Lean body weight
         aCorrection   factor varies with the drug and study findings.

evaluating the effect of obesity in general—let alone specific degrees of obesity or body
composition, or bariatric surgery, or the influence of severe weight loss or extreme weight
cycling—on the disposition and effect of medications. Much of the data is generated
following single dose, rather than multiple chronic doses as used in clinical practice, or
from single case reports or case series often involving heterogeneous groups. It remains
difficult to predict the influence of obesity on drug disposition and effect based solely on
simplistic factors (e.g., drug lipophilicity). Dosing guidelines based on single case reports
or small case series, as described in the previous sections, cannot be made with as much
confidence as those based on more rigorous evaluation in a pharmacokinetic or pharma-
codynamic study.
   One significant area that requires more effort is a method to clinically evaluate body
composition of obese patients, or at least to better evaluate population estimates of body
composition in subgroups of the obese—by gender, ethnicity, degree of obesity. Whole
body densitometry, bioelectric impedance, dual-energy x-ray absorptiometry, and other
methods can be used to determine lean body mass as long as limitations in technique are
accounted for. Estimates may vary depending on data source and patient group (159).
This potential interindividual variability needs to be addressed.
   Another area requiring focus is the determination of individual drug characteristics in
obese individuals—pharmacokinetic and pharmacodynamic. Determine, drug by drug,
the volume of distribution, clearance, and therapeutic effect in each. It may become
important to evaluate drug disposition in patients of similar BMI, body composition, and
even ethnic background. Differing body composition should be examined not just between
degrees of obesity, but also within a group of individuals of the same BMI. The activity of
specific CYP isoforms in pre-obese, obese, and morbidly obese subjects should be docu-
120                                                          Part II / Influence of Nutritional Status

mented. In this way drug regimens may be better suited to an individual patient to maxi-
mize the effectiveness of a drug regimen and limit potential toxicity. Early phase drug
studies for new compounds should account for pharmacokinetic differences by body
   Suggestions made in this chapter regarding the lean body mass equation, use of the
volume of distribution normalized to TBW, and total body clearance between obese and
nonobese individuals needs to be evaluated prospectively.

   The practice of using dosing regimens in the obese patient based on data obtained in
nonobese individuals may increase the risk of drug toxicity or therapeutic failure. Simi-
larly, generalizations cannot necessarily be made about agents from a related class when
data is only available for one of them in obesity. A therapeutic dosing strategy can be
developed for obese patients. Specific volume of distribution and clearance data on a drug
can be used to determine a therapeutic dosing strategy for the drug in an obese patient.
This requires use of drug-specific data in obese individuals (Table 3). Loading doses can
be based on volume of distribution data, instead of simply on degree of lipophilicity, and
maintenance doses can be based on drug clearance data. Weight-based approach to
loading doses will depend on the distribution of the drug in obese individuals as deter-
mined by the volume of distribution per kilogram compared to that in the nonobese
(Table 4). For drugs with a clearance that appears to be correlated with increasing
weight, use TBW for dosing, and of course consider the need to modify dosing intervals
based on pharmacodynamics. On this last point, any available pharmacodynamic data
should supplement recommendations based on pharmacokinetic parameters. Close
patient monitoring is always required.

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Chapter 7 / Drug Absorption With Food             127

128   Part III / Influence of Food or Nutrients
Chapter 7 / Drug Absorption With Food                                                    129

     7           Drug Absorption With Food

                 David Fleisher, Burgunda V. Sweet,
                 and Ameeta Parekh

   Oral input is the most convenient route for drug administration so the large majority
of drug products are oral dosage forms. This dictates consideration of the timing of drug
administration with respect to the time of meal ingestion. There are several reasons for
taking a drug with a meal or nutrient beverage. It may be expedient for clinical staff in
hospitals and assisted living centers to administer a drug at a time when meals are pro-
vided for inpatients. Outpatient compliance with the prescribed drug dosage regimen
may be aided with administration at regular mealtimes. Some drugs are irritating in the
gastrointestinal (GI) tract and their administration with food or a nutrient beverage can
diminish this effect as compared to administration with water.
   For some drugs, meal administration can alter oral drug absorption and, possibly,
therapeutic effect compared to fasted-state drug administration with water. In this regard,
oral drug–meal interactions can be described as pharmacokinetic and pharmacodynamic
   One of the more dramatic pharmacodynamic drug–nutrient interactions (DNIs) with
significant clinical repercussions may occur subsequent to administration of a monoam-
ine oxidase inhibitor drug with meal components containing tryptamine or tyramine. A
depressed patient on oral tranylcypromine therapy who ingests cheese as a meal compo-
nent (1) illustrates a classic example for such an interaction requiring emergency care for
the resultant hypertensive crisis. This extreme example illustrates a direct pharmacologi-
cal interaction in which a meal component alters clinical response to oral drug adminis-
tration dictating marketed product insert warnings and special prescription labeling.
Another interaction in this class occurs when oral anticoagulant therapy is impacted by
the ingestion of sushi, which has a high vitamin K content (2). Such pharmacodynamic
interactions are the topic of another chapter in this text.
   Pharmacokinetic interactions are reflected by meal influences on drug plasma levels
and are the focus of this chapter. Clinically significant changes correspond to maximum
drug plasma levels varying above or below the therapeutic range with meal administra-
tion. These changes are often mediated by a meal effect on the extent of drug absorption
and are most serious for drugs with a narrow therapeutic window for which effective

                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
130                                                   Part III / Influence of Food or Nutrients

under- or overdose critically impacts patient health. Such changes dictate prescription
labeling to take the drug with or without food and health care professional counseling
on the timing of oral drug administration with respect to meal intake. A more common
pharmacokinetic effect is represented by a delay in therapeutic drug concentrations from
meal-induced increases in gastric emptying time without a change in systemic availabil-
ity and extent of absorption. Although this interaction is not of concern for many drugs,
a meal-induced delay in absorption may be a significant clinical event to a patient on an
oral analgesic drug hoping to achieve rapid pain relief.
   Following initial review of this topic (3), a number of recent review articles on drug–
food interactions are available in the literature (4–10). Because this text is intended for
health care professionals as opposed to drug development scientists in the pharmaceuti-
cal industry, this review is geared toward a patient-care perspective. A listing of drug
administration timing with respect to meal effects on the pharmacokinetics of the most
commonly prescribed drugs is provided (Tables 1 and 2). Additionally, guidelines for
clinical meal-effect studies are outlined based on regulatory considerations.

   The potential for a meal to influence drug absorption depends on drug and dosage
form physical–chemical properties as well as meal effects on GI physiology. Drug
properties and the rate of dosage form release of drug into solution in the GI tract define
rate-limiting steps in the drug absorption process. Drug dissolution, intestinal perme-
ability, and gastric emptying determine the rate of absorption. However, both intestinal
and hepatic first-pass metabolism can couple with these absorption rate limits to effect
systemic drug availability. Each of these rate limits can be influenced by meal input.
   The extent of drug absorption is determined by drug residence time at sites of absorp-
tion and sites of chemical degradation and enzymatic metabolism in the GI tract. Some
drugs are unstable in stomach acid so gastric residence time is a critical physiological
variable (11). Because GI pH is region-dependent and ionizable drug solubility is a
function of pH, drug dissolution and precipitation can impact drug availability in solution
for absorption. Furthermore, GI pH can affect intestinal permeability of ionizable drugs.
Both drug intestinal permeability and metabolism may be saturable as well as region-
dependent so at a given dosage, administered fluid volume, gastric emptying, and intes-
tinal transit combine to play a role in rate and extent of drug absorption. Each of these
variables can be influenced by meal input.

2.1. Drug Absorption Dependence on Drug Properties
   Drug aqueous vs lipid solubility are key properties in determining rate limits to intes-
tinal absorption of drugs. Many drugs owe some of their potency to their ability to
permeate cells membranes and gain access to sites of pharmacological action. Good
membrane permeability is generally a function of good lipid solubility (lipophilicity).
This is accompanied by poor hydrophilicity (referring to aqueous solubility) so the absorp-
tion rate of these drugs is limited by poor dissolution into the aqueous media of the GI tract.
Dosage formulation can sometimes reduce this problem because drug dissolution rate
also depends on the powder drug surface area exposed to water. Drug powder surface area
can be increased by micronization and for a low-dose (0.25 mg) drug like digoxin; this
Chapter 7 / Drug Absorption With Food                                                                    131
Table 1
Medications to be Administered on an Empty Stomach
 Generic Name                   Brand Name                           Clinical Effect/Reason
   Alendronate                 Fosamax                       Dairy products/food can impair
   Etidronate                  Didronel                       absorption; administer 2 h prior to meal
   Risedronate                 Actonel
Captopril                      Capoten                        Food decreases absorption; administer
                                                              1h before or 2 h after a meal
Cefaclor                       Ceclor                        Food delays absorption; take 1 h before
                                                             or 2 h after a meal
Dextroamphetamine              Adderall                      Acidic foods/juices will impair
Digoxin                        Lanoxin                       Food delays absorption; take consistently
                                                              with respect to meals
Diltiazem                      Tiazac, Cardizem              Increased absorption in the fasting state;
                                                              administer before meals
Furosemide                     Lasix                         Increased absorption in the fasting state
Glipizide                      Glucotrol XL                  Increased absorption and improved
                                                              clinical effect when administered 30
                                                              min prior to meal
Levothyroxine                  Levoxyl, Synthroid            Increased absorption in fasting state; take
                                                              at same time daily and consistently
                                                              with respect to meals
Phenytoin                      Dilantin                      Food alters absorption; take consistently
                                                              with respect to meals
Proton pump inhibitors
   Esomeprazole                Nexium                        To improve absorption and maximize
   Lansoprazole                Prevacid                       clinical effect, administer before
   Omeprazole                  Prilosec                       meals
   Pantoprazole                Protonix
   Rabeprazole                 Aciphex
   Ciprofloxacin               Cipro                         Cations (Ca, Fe, Zn, etc.), antacids, and
   Norfloxacin                 Noroxin                        dairy products will decrease
Tetracyclines                                                    absorption
   Minocycline                 Minocin                       Absorption significantly impaired by
   Tetracycline                Sumycin                        iron/milk/food
Theophylline                   TheoDur, TheoBid,             Food may decrease absorption; take
                               SloBid                         consistently with respect to meals
Warfarin                       Coumadin                      Food alters absorption; take consistently
                                                              with respect to meals
Zafirlukast                    Accolate                      Food decreases absorption
   Note: List is based on 2001 top 200 brand/generic prescribing by prescription volume. Note that drug–
food interactions may exist for other medications not included on this list (e.g., anti-HIV medications). Many
medications also have interactions with grapefruit juice.
   Ca, calcium; Fe, iron; Zn, zinc.
132                                                            Part III / Influence of Food or Nutrients

Table 2
Medications to be Administered With Food
 Generic Name                   Brand Name                           Clinical Effect
Carbamazepine                 Tegretol                   Food increases absorption
Divalproex                    Depakote                   Decreased GI upset
Fenofibrate                   Tricor                     Increased bioavailability
Glyburide/metformin           Glucovance                 Decreased GI upset from metformin
Labetalol                     Normodyne                  Food increases absorption; take consistently
                                                            with respect to meals
Metformin                     Glucophage                 Decreased GI upset
                                (reg and XR)
Metoprolol                    Toprol, Toprol XL          Food increases absorption; take consistently
                                                           with respect to meals
Nitrofurantoin                MacroBid                   Improved tolerance and increased
Potassium chloride            K-Dur, Klor-Con            Decreased GI upset
Tamsulosin                    Flomax                     Food alters bioavailability; take consistently
                                                           30 min after same meal daily
Venlafaxine                   Effexor                    Decreased GI upset
   Note: List is based on 2001 top 200 brand–generic prescribing by prescription volume. Note that drug/
food interactions may exist for other medications not included on this list (e.g., anti-HIV medications). Many
medications also have interactions with grapefruit juice.
   GI, gastrointestinal.

greatly improves drug absorption into the systemic circulation. Some increase in absorp-
tion via micronization is observed for a high-dose (500 mg) drug like griseofulvin, but
the improvement is only modest. Enhancing drug absorption through increased dissolu-
tion surface area depends on the amount of drug that can be dissolved within the small
intestinal transit time. This is, of course, more difficult to achieve at higher doses.
   As would be expected, many lipophilic drugs are better absorbed when administered
with a meal that has fatty components. Absorption may increase as a direct function of
meal fat content. A good example of this is the first-marketed HIV-protease inhibitor,
saquinavir. This drug was approved quickly despite the fact that an oral dose adminis-
tered with water resulted in only 5–10% of this high-dose drug reaching the systemic
circulation. It was observed that when patients took this medication with a high-fat meal,
systemic availability increased 5- to 10-fold. Newer dosage forms take advantage of this
by putting the drug in a lipid vehicle inside a soft-gel capsule (12).
   Hydrophilic drugs possess good aqueous solubility and dissolve quickly but do not
permeate lipid membranes very readily. The absorption of these drugs is therefore rate-
limited by membrane permeability rather than dissolution. Coadministration with meals
does not typically affect the absorption of hydrophilic drugs. Some hydrophilic drugs are
exceptional and have high membrane permeability due to membrane transport by nutrient
carriers. Several amino acid and small peptide drugs fall into this category. Although it
might be anticipated that protein meals would inhibit the absorption of these drugs, this
has not been observed in clinical practice (13).
Chapter 7 / Drug Absorption With Food                                                   133

   Another class of hydrophilic drugs with good membrane permeability includes com-
pounds of sufficiently small molecular size (< 200 Daltons) that they permeate membrane
paracellular pathways. Because neither dissolution rate nor membrane permeation is
rate-limiting to absorption, gastric emptying controls the rate of absorption of these
smaller drugs. The effect of meal intake on gastric-emptying rate is a point discussed in
a later section of this chapter. The analgesic drug, acetaminophen, falls into this class of
compounds (14).
   Drugs may also have both poor dissolution rates and poor membrane permeability.
Such drugs are not poorly water soluble because they are lipophilic but rather because
they have a high capacity to form intermolecular hydrogen bonds. Such compounds tend
to have high melting points and form poorly dissolving crystals. Although food can
negatively affect the absorption of such compounds, they rarely make it to the market as
oral drug products because their properties dictate poor oral absorption even in the fasted
state (15).

2.2. Drug Absorption Dependence on Dosage Form Properties
   The most clinically significant food effects on oral drug delivery have been in asso-
ciation with the administration of extended or modified release-dosage formulations of
narrow therapeutic window drugs (16–18). Because these formulations typically contain
very high doses of high permeability drugs, meal-component interactions with formula-
tion components that alter the intended release rate can produce an effective under- or
overdose. In the extreme, meal-induced “dose dumping” as a bolus drug-release process
of the entire dose of a modified-release formulation can result in toxicity in individual
patients (19).
   Less dramatic meal effects on modified-release dosage forms are seen as meal-con-
trolled delays in oral drug delivery to the systemic circulation. Because non-disintegrat-
ing particles greater than 2 mm in diameter do not empty from the stomach with the gastric
liquid contents (20), oral drug delivery from dosage forms with these properties may be
influenced by meal intake. Such dosage forms are subject to emptying with the timing of
the interdigestive migrating motility complex (IMMC) under the control of the circulat-
ing gut peptide, motilin (21). Following administration of a meal, this complex is dis-
rupted and gastric emptying is influenced by other gut peptides (22) as regulated by
caloric density and intestinal feedback control (23). Gastric emptying control by IMMC
is not re-established until most of the meal calories have been emptied. As a result, with
high-caloric density input, gastric emptying of nondisintegrating dosage forms greater
than 2 mm in diameter may experience substantial time lags before emptying into the
intestine and absorption delays may be reflected in delayed drug plasma levels (24).

2.3. Meal Effects on GI Transit and Drug Absorption
   Although mean small intestinal transit time (between 3 and 4 h) is remarkably inde-
pendent of fasted vs fed-state conditions (25) several drugs (26,27), drug excipients (28),
and over-the-counter products (29) have been shown to influence the extent of drug
absorption via influences on intestinal transit. Careful studies have shown that a drug’s
small intestinal residence time in human subjects is in the range of 200 min whether it is
administered with or without a meal (25). However, gastric emptying rate is a function
of both volume and caloric density.
134                                                   Part III / Influence of Food or Nutrients

   In many studies of meal effects on drug absorption, a comparison of fasted vs fed
conditions is not controlled for administered volume (9). This is certainly consistent with
the variability in patient fluid intake with oral drug administration of prescription drugs
and may therefore represent a legitimate statistical comparison. Although such studies
may verify whether or not there is a significant food effect on oral drug bioavailability,
fasted-state pharmacokinetics may depend on administered volume for several reasons.
When a drug is administered with a noncaloric aqueous liquid, the rate of human gastric
emptying of liquid containing dissolved drug and small drug particles is first-order and
dependent on volume load after an initial lag period. When a drug is administered with
small volumes of fluid in the range of 2 fluid ounces (60 mL), emptying of the gastric
contents is more dependent on the IMMC than is the case when larger volumes in the
range of 8 fluid ounces (240 mL) are administered (30). Thus, emptying of a drug con-
tained in the gastric fluid contents will be more erratic with respect to the time of drug
administration for smaller than larger coadministered fluid volumes. Additionally, the
first-order gastric emptying of larger volumes is more rapid than for smaller volumes for
all phases of the IMMC.
   Meal administration is typically high volume, but intestinal feedback control dictates
that gastric emptying rate and resultant drug delivery to absorption sites in the small
intestine is a function of caloric load or density (calories per volume administered).
Furthermore, if fasted-state drug administration is conducted under low-volume condi-
tions compared to the typical high volumes consumed with meal administration, initial
intestinal drug concentrations will be much higher in the fasted-state condition as com-
pared to meal coadministration. Additionally, certain meals may dictate significant gas-
tric, intestinal, biliary, and pancreatic secretions that can further dilute fed-state drug
concentrations as compared to the fasted state. For those drugs that show nonlinear
characteristics as a function of local concentrations, such differences in the volume of
administration can complicate the interpretation of food-effect studies. It would be
advisable to administer the same volume of noncaloric fluid in fasted-state studies as
the volume of meal administered in fed-state studies. Although this only controls initial
conditions, because meals will influence GI fluid absorption and secretions, a more
mechanistic comparison is offered when meal effect studies control for volume.
   Caloric feedback signals from the intestine that control gastric emptying have been
studied for simple carbohydrate, fat, and protein meals. Triggers for these signals include
sodium-monosaccharide cotransport (31), peptide digestion (32), and chylomicron for-
mation (33). The magnitude of the signal and the extent of gastric-emptying inhibition
are a function of the extent of nutrient and intestinal sensor contact down the length of
intestine (34,35) and therefore depend on both digestion and initial caloric load. The
pattern of calorie-regulated gastric emptying is different than for volume-controlled
gastric emptying (30) and has been studied in most detail for simple glucose meals (36).
With respect to oral drug delivery, calorie intake will result in a different volumetric input
rate of gastric-liquid-containing drug into the intestine than for noncaloric liquid intake.
This will, in turn, influence differences in rates of coadministered drug delivery to sites
of absorption and first-pass elimination in the upper intestine with nutrient vs noncaloric
Chapter 7 / Drug Absorption With Food                                                      135

input. Caloric control of intestinal drug delivery rates from gastric emptying can result
in less variability in oral drug pharmacokinetic profiles compared to drug administration
with small volumes of noncaloric fluid. This is the case because the timing of gastric
emptying with an IMMC will be highly variable with respect to the time of oral drug
2.3.3. MEAL TYPE
    Although different meal types provide a similar rate of fluid delivery from the stomach
to small intestine based on caloric density (37), intestinal fluid volumes and resultant drug
concentrations depend strongly on meal type. Simple carbohydrate meals may result in
substantial water absorption in the small intestine (38) that may, in theory, result in more
concentrated drug solutions in the intestinal lumen. Protein meals promote higher intes-
tinal fluid volumes as the result of significant pancreatic secretions (32) that may, in
theory, result in more dilute drug solutions. Even greater intestinal volumes should result
from intake of high-fat meals because pancreatic and biliary secretions will be stimulated
to a greater extent than with other meal types (39). The fed-state balance between intes-
tinal fluid secretion and intestinal water absorption is very much a function of the rate at
which complex meals are converted to simple nutrients. Simple carbohydrates tend to be
rapidly broken down in the upper GI tract, whereas protein and fat digestion are slower
processes (39). The greater extent of upper intestinal water absorption observed with
simple carbohydrate meals as compared to protein meals is the result of both differences
in the rate of digestion and differences in the absorption pathways of the resultant elemen-
tary nutrients. Most monosaccharides are absorbed by sodium-dependent cotransporters
that promote intestinal water absorption (40). Although a number of sodium-dependent
transporters support amino acid transport, many intestinal amino acid transporters utilize
sodium-independent mechanisms for mucosal absorption (41).

2.4. Physical Chemical Interactions in the GI Tract
  Absorption of drugs that are coadministered with meals may be altered both by meal-
component influences on GI physiology as well as meal-component influences on drug
and dosage form properties.
   Although this factor is certainly related to meal type based on digestibility, the fact that
meal viscosity can be studied independent of caloric input dictates consideration as an
additional meal-effect factor. A clinical example is provided later in the chapter. As
opposed to the effect of high fluid volume intake resulting in local gastric pressure
distention, which speeds gastric emptying, high viscosity intake slows gastric emptying
(42). If insufficient digestion occurs in the gastric contents to substantially reduce the
solution viscosity entering the small intestine, several factors may effect drug absorption
following oral administration. First, higher viscosity may increase upper intestinal resi-
dence time. Additionally, based on the inverse dependence of solute diffusivity on
medium viscosity, diffusion of dissolved drug from the intestinal lumen to sites of
absorption at the intestinal membrane will be slowed. Finally, high viscosity can
slow drug dissolution rate by decreasing solute diffusion away from the solid drug
surface (43).
136                                                   Part III / Influence of Food or Nutrients

   Medium pH can impact both the solubility and membrane permeability of ionizable
drugs. Because meal intake may alter gastric and upper intestinal pH, the ionization
state of weak acid and weak base drugs with pKa in the range of GI pH variation will be
affected. Because nonionized drug has greater membrane permeability than an ionized
drug, nutrient effects on mucosal microclimate pH might be expected to influence the
absorption of drugs in this class. Enterocyte metabolism of glucose lowers microclimate
pH via sodium–proton exchange (44). However, little overall effect on drug absorption
is observed.
   Food effects on weak acid drugs are not common (4), because ionized drugs promote
high solution concentrations in the intestine and permeability of the nonionized com-
pound is frequently high enough to shift ionization equilibrium toward favorable absorp-
tion. The previously marketed nonsteroidal anti-inflammatory drug (NSAID), bromfenac,
may be exceptional in this regard (45). This drug showed a reduced analgesic effect when
administered with a meal. This unusual meal effect for a weak acid drug with a pKa within
GI pH variation may be a function of bromfenac’s exceptionally low dose as compared
to other NSAIDs.
   The potential for meal effects on weak base drugs, with pKa in the range of GI pH
variation, is greater than for weak acids. This is a function of their potential to precipitate
at intestinal pH or high gastric pH as promoted by some types of meals (46). A clinical
example is provided later in the chapter.
   There is experimental evidence that the stomach controls the rate of soluble calcium
delivery to the small intestine. This element of intestinal feedback control has been
verified indirectly by observations on the rate of gastric emptying of calcium chelators.
The observation of feedback control appears to be an indirect effect of the capacity of
calcium chelators to remove ionic calcium from the tight junctions (31). In isolated
intestinal tissue and cell culture, removal of calcium from the tight junctions may result
in an increase in paracellular solute transport (47). A defense mechanism to slow the
delivery of calcium chelators from the stomach would thus serve a protective feedback-
control function. Because a number of elementary nutrients resulting from fat digestion
sequester calcium (31), this may provide a parallel feedback control mechanism to that
of caloric content in controlling the rate of gastric emptying. Additionally, to the influ-
ence of this factor on the rate of gastric delivery to the small intestine and the availability
of the paracellular pathway for absorption, calcium is known to bind a number of drugs,
like tetracycline, reducing their availability for absorption in the intestine (48).
   Drug binding, complexation, and micellar sequestration, including bile acid interac-
tions, can reduce effective drug concentration in the intestinal lumen and can reduce
absorption. Over-the-counter product effects including antacid effects on drug binding,
oil emulsion product effects on drug sequestration, and fiber effects on viscosity may
mediate a number of these interactions.
   Drug binding to nutrient components has been most often cited with drug coadmin-
istration with enteral nutrient products. These interactions may include both reversible
Chapter 7 / Drug Absorption With Food                                                     137

and irreversible binding components when drug–nutrient coadministration is through
nasogastric tubes (49). Drug binding to the protein component of common enteral nutri-
ent feeding products has also been reported (50).
    The significant clinical impact of grapefruit juice on the oral bioavailability of several
drugs (51) brought meal-component effects on first-pass drug elimination to the forefront
of food-effect studies. This is an example of a meal component directly inhibiting the
activity of first-pass elimination factors dictating an increase in oral bioavailability. Such
inhibitory effects can lead to dramatic increases in oral drug delivery (52). Meal input can
influence drug first-pass elimination elements through saturation as well as inhibition. It
has been stressed that oral drug dosage form administration factors, including
coadministered meals, influence drug concentration gradients that are the driving forces
for drug absorption. For example, meal lipid solubilization of an orally administered drug
may serve to increase lipophilic drug concentration in the GI lumen. Oral bioavailability
is further determined by intestinal and hepatic biological components with activities that
may or may not be saturated as a function of local drug concentration gradients. By
impacting local drug concentration gradients around first-order to zero-order transition
points for saturable absorption and first-pass elimination components, meals can exert an
effect on oral bioavailability independent of inhibition on first-pass elimination. First-Pass Metabolism. Meals can affect both intestinal and hepatic first-
pass metabolism. With regard to nutrient component inhibitory effects, phase I pathways
have been observed to be impacted to a greater extent than phase II pathways (53).
Because grapefruit juice inhibits cytochrome P450-3A4 (CYP3A4), which has been
shown to be responsible for the intestinal metabolism of the greatest number of drugs and
drug candidates, this elimination element has been the focus of DNI studies. Drug can-
didate screening now includes human hepatocyte, microsomal, or recombinant enzyme
metabolism data. Because CYP3A4 is a component of this screening, a measure of the
potential for intestinal metabolism is also available. Caco-2 monolayers enhanced in
CYP3A4 have been developed to screen drug candidate intestinal metabolism coupled
to membrane transport control factors (54). Basic studies to isolate the grapefruit juice com-
ponent responsible for CYP3A4 inhibition has generated broader investigations of elemen-
tary nutrient factors that might impact this important drug-metabolizing enzyme (55).
    Other drug-oxidizing enzymes in the intestine (56) and liver (57) may be influenced
by nutrient intake. In animal studies, it was reported that methionine and cysteine inhib-
ited flavin monooxygenase (FMO)-mediated cimetidine sulfoxidation (58). This inter-
action is less important in humans and cimetidine’s safety further reduces clinical
significance. The absorption of a narrow therapeutic index drug that undergoes FMO-
mediated sulfoxidation, has been shown to not be influenced by meal intake (59). How-
ever, for a new drug entity, the screening of a battery of metabolizing enzymes and further
basic investigations on elementary nutrient effects on metabolism may yet uncover meal
effects on drug metabolizing enzymes other than CYP3A4 (see Chapter 2). Intestinal Export Permeability Limitations. Current research has impli-
cated P-glycoprotein (P-gp)-mediated drug export as a factor limiting intestinal perme-
ability of some compounds (60) and has led to further investigations on the effect of
nutrients on this elimination pathway (61). Inhibition of P-gp by dietary flavanoid com-
138                                                  Part III / Influence of Food or Nutrients

ponents has been reported (62). Because P-gp substrates are typically hydrophobic and
poorly water soluble, saturation of P-gp is difficult to achieve. However, elevated drug
concentrations through meal-lipid solubilization could lead to a nonlinear concentration
dependence of P-gp-mediated drug export (63). For lipophilic compounds that are P-gp
substrates, the combined effects of increased permeability via P-gp inhibition with an
increase in drug concentration through solubilization by a high-fat meal might be pro-
jected to substantially increase absorptive flux. Most P-gp substrates are neutral or weak-
base hydrophobic compounds (64). Some weak acid drugs are substrates for intestinal
multidrug-resistance proteins and/or multispecific organic anion transporters such as
cMOAT (65). There may be additional intestinal membrane proteins mediating drug and/
or drug metabolite export yet to be identified that could interact with the nutrient com-
ponents of a meal (66).
    There is evidence that drug metabolites are substrates for intestinal exporters and it is
proposed that intestinal metabolism and mediated mucosal export are coupled processes
in intestinal drug elimination (67). The function of such coupling, with respect to CYP3A4
and P-gp, is suggested to promote efficient intestinal elimination (68). Because most
metabolites are less hydrophobic than their parent drug, they might be weaker substrates
for P-gp. Efficient intracellular metabolite production would set up a favorable metabo-
lite-to-drug ratio, minimizing potential competition for P-gp export (69). Some inhibitors
of P-gp are also inhibitors of CYP3A4, and these include some compounds that are meal
components (70,71). Given the possibilities of inhibition and saturation of coupled intes-
tinal drug-elimination components, the impact of meal intake on first-pass metabolism
may be mechanistically complex.
   Many drugs possess sufficient lipophilicity to promote high permeability throughout
the small and large intestine (72,73). However, for some compounds, intestinal absorp-
tion and elimination may not be homogeneous or even continuous processes throughout
the entire small intestine. This is the case for some drugs that are absorbed by a carrier-
mediated process (74) and is generally true for drugs of moderate lipophilicity as a
function of a reduction in absorbing surface area in the lower small intestine (75). For
small hydrophilic compounds predominantly absorbed through paracellular pathways, it
would be anticipated that permeability would decrease with distance down the intestine
because paracellular pathways become more restricted by the tight junctions (76). How-
ever, this has not been confirmed with the paracellular marker compound mannitol (77)
and regulation of this pathway may be variable as a function of intestinal region (78).
What may prove to be a significant factor in regionally dependent drug absorption are
differences in drug elimination as a function of intestinal region (69). Furthermore,
resultant differences in the rate of absorption and elimination in different regions of the
intestine can dictate variability in the rate of drug presentation to the liver.
   Recent studies indicate that region-dependence in the absorption of some drugs may
underlie a significant meal effect on systemic drug availability following oral adminis-
tration (69,79). When drug absorption is better in the upper small intestine than in the
middle and lower regions, meal factors that serve to reduce drug availability to the
absorbing membrane may produce negative effects on systemic availability. These fac-
tors may include drug-binding interactions with meal components or any physical hin-
Chapter 7 / Drug Absorption With Food                                                        139

drance to drug transport provided by meal intake in the upper intestine that reduces drug
availability to sites of absorption. Reduced drug absorption in the upper intestine can
result in delivery of lower drug concentrations to sites of first-pass elimination. It is
possible that drug administration without meals may provide intestinal concentrations
sufficient to saturate first-pass metabolism, whereas administration with a meal results in
drug concentrations below first-pass saturation levels. Based on a limited set of studies, the
potential for a negative meal effect is more likely if there is region-dependent absorption.
   Just as nutrient effects on region-dependent drug absorption should alter rate of drug
delivery to sites of first-pass elimination, meal effects on splanchnic blood flow would
be anticipated to alter the rate, and possibly extent, of first-pass drug elimination. This
may be the case with meal effects on alcohol elimination and possibly underlie varying
meal effects on high first-pass drugs like propranolol.

   The first HIV-protease inhibitor on the market was saquinavir. The need for treatment
with this drug class dictated approval despite a low 5% oral bioavailability. This was
because of the low intrinsic solubility and high first-pass metabolism of this drug.
Although orally administered as a mesylate salt at 600–800 mg three times a day, this
low pKa weak-base drug may dissolve in the acid pH of the stomach but would enter the
upper small intestine at concentrations three orders of magnitude above its intrinsic
solubility. Such a high level of supersaturation would promote the potential for intestinal
precipitation. Observations that saquinavir administration with a high-fat meal increased
oral bioavailability 5- to 10-fold (80) led to the development of a lipid-melt soft-gel
capsule formulation that similarly increased oral bioavailability (12). This tremendous
increase in bioavailability, as a function of dosage formulation, is likely owing to a
combination of solubilization of the drug in the intestine by lipid meal components and
the resultant saturation of some elements of first-pass elimination, particularly in the
intestine. Saturation of intestinal CYP3A4 and P-gp should result in a faster rate of
absorption and a higher rate of drug presentation in the portal vein to the liver.
   The third drug marketed in this class of compounds was indinavir, which showed a
decrease in bioavailability when administered with meals (81). Goals in the molecular
design of this drug included the addition of a weak-base moiety with higher pKa to
increase its solubility. It is administered as a sulfate salt at a dosing regimen similar to that
of saquinavir. As was the goal of this molecular design ploy, it is likely that indinavir
achieves higher concentrations in the GI tract and a higher driving force for absorption
as compared to saquinavir when administered without meals. The higher intestinal
indinavir concentrations compared to saquinavir saturate elements of first-pass elimina-
tion resulting in oral indinavir bioavailability 10-fold higher than the initial saquinavir
product. However, when the drug is administered with a high-caloric meal, a 60% reduc-
tion in indinavir bioavailability is observed. When the drug is administered with a light
meal of low caloric density, the meal effect can be minimized (81).
   Possible contributions to a negative meal effect on indinavir were investigated in HIV-
infected patients as a function of meal type (46). Indinavir plasma levels and gastric pH
were simultaneously measured as a function of time after oral indinavir administration.
140                                                   Part III / Influence of Food or Nutrients

In this clinical study, protein meals produced the greatest and most statistically consistent
reduction in oral indinavir bioavailability as compared to administration with an equal
volume of water. Gastric pH, as measured by radiotelemetry in these patients, showed
that the protein meal caused a lengthy (4 h) pH elevation (around pH = 6.0 over this time
period) as compared to other meal types or drug administration with water. Only slight
pH elevations of short duration were observed with the other meals because they offer
little buffer capacity to gastric acid secretion. It is suggested that the protein meal will
provide the greatest potential for poor dissolution and/or precipitation of indinavir in the
stomach as a function of elevated pH.
    However, all meal types produced a significant negative meal effect on indinavir oral
bioavailability, although not to as great an extent or as consistently from patient to patient
as the protein meal. Meal types studied in addition to the high-caloric protein meal
included high-caloric carbohydrate and high-caloric lipid meals as well as a noncaloric
viscous meal. It is likely that high-caloric density meals, as well as high-viscosity meals
slow gastric emptying and the rate of drug transport in the intestinal lumen to sites of first-
pass elimination to an extent that they are no longer saturated.
    Other contributions to the negative meal effect have been investigated in isolated
animal and tissue experiments to include influences of intestinal regional differences
(69). In the case of indinavir, rat intestinal perfusion studies show high permeability in
the upper intestine and dramatically reduced permeability in the lower small intestine.
The drug is metabolized by CYP3A4 in both the upper intestine and liver and the pre-
dominant intestinal metabolite is excreted into the intestinal lumen. Interestingly, no
metabolism is observed in lower small intestine and metabolism is greatly reduced in the
mid-jejunum as compared to the upper jejunum. Indinavir is also a substrate for intestinal
P-gp and this may account for its poor permeability in the lower intestine where P-gp
exports drug that is absorbed into the enterocyte back to the intestinal lumen. The fact that
CYP3A4 metabolism dominates indinavir elimination in the upper small intestine while
P-gp secretion controls its elimination in the lower small intestine permits some mecha-
nistic studies in the rat. Reaction-coupled transport in the form of cellular metabolism
subsequent to cell entry increases the rate of indinavir absorption into the enterocyte by
increasing the concentration-gradient driving force for cellular entry. If metabolite
export competes with drug export by P-gp, this could promote drug absorption across
enterocytes in the upper small intestine while there would be no such competition in the
lower small intestine (69).
    Continued elimination as the drug moves down the intestine will depend on regional
CYP3A4 and exporter activity as well as on changes in drug concentration down the
intestinal tract. Meal effects on the rate of drug delivery to these sites of first-pass elimi-
nation might be anticipated to produce alterations in bioavailability. The potential for a
positive meal effect from lipid-enhanced solubility compared to negative meal effects via
slowing delivery to saturable sites of first-pass elimination may also be determined by
variation in these elimination factors as a function of intestinal region. Some evidence for
this might be gleaned by a comparison of indinavir with nelfinavir, the fourth HIV-
protease inhibitor to reach the prescription marketplace. Nelfinavir shows a positive meal
effect similar to saquinavir (82). In rat intestinal perfusion of upper jejunum compared
to lower ileum, nelfinavir showed no region-dependent permeability as compared to the
dramatic regional permeability differences just cited for indinavir (69).
Chapter 7 / Drug Absorption With Food                                                     141

   Food and drug intakes often coincide, because meals habitually serve as temporal
reminders to patients of timely drug administration. Drugs may also be intentionally
coadministered with meals to minimize GI side effects, a common practice for certain
drug classes (e.g., NSAIDS). Administration of drugs concomitantly with or in close
proximity to meals could result in a significant increase or decrease in the overall rate and
extent of drug absorption and, as a consequence, may occasionally compromise efficacy
or lead to adverse effects. These situations justify drug administration under a fasted state.
Theo-24, which is a specific once-daily theophylline product, and alendronate, which is
a bisphosphonate for improving bone mineral density are examples in this category (83).
On the other hand, when changes in the rate and extent of absorption lead to lower side
effects or improved efficacy, concomitant administration with meals is desirable and is
generally recommended (e.g., atovaquone) (83). Often, changes in rate and extent of drug
absorption resulting from food–drug interactions are unlikely to be clinically significant.
In such cases, Food and Drug Administration (FDA)-approved labels are either silent
with respect to how the drug should be administered, or may state that the drug could be
taken without regard to meals (e.g., loratadine) (83). Regulatory agencies generally make
these assessments and recommendations after reviewing food-effect bioavailability stud-
ies for new drug applications (NDAs), factoring in their exposure-response relationships
and clinical safety and efficacy database submitted with the sponsors’ registration dossier.
   Food intake may influence drug exposure owing to the effect that meal components
have on the physiological system, which, in turn, may influence absorption (e.g., grape-
fruit juice inhibits CYP3A4-mediated drug metabolism, high-fat, high-calorie meals
prolong gastric emptying time and may also affect drug solubility). Drugs may also
physically or chemically bind to specific food items (e.g., digoxin bioavailability may be
lower with a high-fiber meal) and as a result may affect drug exposure. In the following
sections, guidelines for meal-effect studies are provided from a regulatory perspective.

4.1. Drug Classification and Food Effects
   Various physicochemical and physiological bases for food–drug interactions have
been alluded to in this chapter (i.e., including delayed gastric emptying, secretions affect-
ing GI pH and solubilization, changes in splanchnic blood flow, meal components affect-
ing metabolism or transport systems, and chelation or complexation processes). Prediction
of changes in drug exposure due to GI perturbations have been attempted using the
Biopharmaceutics Classification System (BCS) of drugs (Table 3) (84). It has been
postulated that important food effects on bioavailability are least likely to occur with
many rapidly dissolving, immediate-release drug products containing highly soluble and
highly permeable drug substances (BCS class I). This is thought to be a consequence of
pH- and site-independent absorption of Class I drug substances, their insensitivity to
differences in dissolution and their extensive absorption (85). Because the proximal
intestinal region is the primary site of drug absorption, a Class I drug may undergo
delayed absorption owing to meal-related prolonged gastric emptying time (resulting in
longer Tmax and lower Cmax) with an overall unchanged extent of absorption (area under
the concentration-time curve [AUC]), (e.g., immediate release theophylline) (86). This
142                                                 Part III / Influence of Food or Nutrients

                 Table 3
                 Biopharmaceutics Classification System
                  Class     Solubility    Permeability      Examples
                    I          High          High         Acetaminophen
                    II         Low           High         Phenytoin
                    III        High          Low          Cimetidine
                    IV         Low           Low          Amphotericin B
                    From ref. 84.

concept seems to hold true unless the drug undergoes high first-pass elimination, is highly
adsorbed, complexed or unstable in the gastric milieu. Immediate-release propranolol
and metoprolol are BCS Class I drugs that undergo high first-pass elimination. A large
increase in the extent of absorption is observed when these drugs are administered with
food (87). The latter is partly attributable to the splanchnic blood flow changes caused
by meal intake. Because dissolution of low solubility drugs may be enhanced with food,
bioavailability may be superior, if taken with meals (e.g., carbamazepine) (88). In gen-
eral, however, for immediate-release drug products of BCS Classes II, III, and IV with
low solubility or low permeability, food effects are most likely to result from a more
complex combination of factors that influence the in vivo dissolution of the drug product
and/or the absorption of the drug substance. In all cases, because the relative direction
and/or the magnitude of food effects on formulation bioavailability are difficult to pre-
dict, and because the regulatory agency assesses the clinical implications of this change,
a food-effect study is recommended for all new chemical entities, irrespective of their
    Formulation factors are expected to play a minor role in bioavailability of Class I drug
products because they rapidly dissolve in a wide pH-range environment and the drug is
well absorbed. Although food can affect Cmax and Tmax by delaying gastric emptying and
prolonging intestinal transit time or in certain instances increasing bioavailability, the
food effect on these measures are expected to be similar for different formulations of
the same Class I drug, provided they have a rapid and similar dissolution. As a result,
these products should be bioequivalent under both fasted as well as fed conditions.
Although an increase in exposure is observed for propranolol and metoprolol when
concomitantly administered with meals, various immediate-release formulations were
shown to be bioequivalent under both fasted and fed conditions. In the case of Class II,
III, and IV drugs, excipients or interactions between excipients and the food-induced
changes in gut physiology can contribute to food effects and consequently may influence
the demonstration of bioequivalence (89). When new formulations are developed with
the intention of switchability, appropriate documentation of therapeutic equivalence (90)
is therefore required.
Chapter 7 / Drug Absorption With Food                                                  143

4.2. Food Effects on Modified Release Formulations
   Administration of a drug product with food may change the bioavailability by affect-
ing either the drug substance or the formulation. In practice, it is difficult to determine
the exact mechanism by which food changes the bioavailability of a drug product without
performing specific mechanistic studies. The underlying BCS principles for food-effect
expectations apply primarily to immediate-release formulations where the drug is released
instantaneously from the dosage form. In these instances, solubility and permeability limit
the rate of absorption. Unlike the conventional immediate-release formulations, modi-
fied-release products are specially designed in that the formulation and manufacturing
variables control the release rate of the drug from the dosage form. As a consequence,
these factors may play a key role in determining the outcome of a food-effect
bioavailability study, irrespective of the BCS classification of the drug substance. Sys-
temic availability of a drug from the modified-release product under fed conditions is
complex. It consists of a combination of the physiological effects of meals on drug release
(affecting disintegration, dissolution, degradation, or diffusion) from these dosage forms,
as well as the effect of meals on drug absorption, once it is released from the modified-
release product.
   Modified-release oral dosage forms (e.g., sustained-release, delayed-release prod-
ucts) are predominantly designed to provide a therapeutic advantage over conventional
immediate-release formulations such as curtailing frequent dosing intervals, minimizing
peaks and troughs in plasma concentrations and overcoming the instability in the gastric
pH. During the late 1970s to early 1980s, extensive experience with development of
several modified-release dosage forms demonstrated that integrity of these products in
the physiological environment of a fed state could present a challenge for formulation
scientists. Theophylline is a noteworthy example for which a number of modified-release
preparations were tested. Owing to its narrow therapeutic window of use, food effects on
formulation robustness drew considerable attention of the scientific community. Although
theophylline immediate-release formulation has a minimal food effect on the overall expo-
sure, when formulated as modified-release formulations, these effects were formulation
dependent. For instance, it was shown that rate as well as extent of absorption were
increased when Theo-24 was administered with a high-calorie meal (about 800–1000
calories with 50% derived from fat), yet a light meal had a minimal effect. Temporal
separation of meals and drug administration helped minimize the food effect. In another
instance, although absorption from Theo-Dur sprinkles was reduced, food effect from
Theobid-Duracap remained unchanged (16).
   Modified-release products may contain large amounts of drug, designed to be deliv-
ered over a prolonged period of time. Lack of formulation integrity or robustness may
bear on its safe and effective use. Findings from modified-release theophylline studies
during the 1970s and 1980s served as a testimony to this concern and re-enforced the need
for thorough in vivo formulation evaluation before proceeding with further drug devel-
opment. In fact, for regulatory purposes at the FDA, oral modified-release dosage forms
are required to demonstrate lack of dose dumping, a phenomenon exemplifying the
untimely release of an undesirable and unintended amount of drug from the modified-
release dosage form (91). To date, in vitro tests have not been consistently predictive of
144                                                   Part III / Influence of Food or Nutrients

either the extent of in vivo food effect or the dose dumping with the modified-release
formulations. The FDA, therefore, recommends that a tangible in vivo food-effect study
be conducted with all new modified-release formulations. This study serves to fulfill the
regulatory requirement of a test for dose dumping. Sponsors of all modified-release
dosage forms generally conduct one or more food-effect studies with the formulation
under development. When food effect is identified, sponsors generally attempt to under-
stand the source of interaction (i.e., whether food effect is owing to the drug substance
or formulation). For certain drug products, insight into the temporal relationship between
food and drug intake and impact of different meal types on drug exposure may be deemed
clinically useful. The sponsors are encouraged to understand this relationship and when
appropriate, to specify these in the dosage and administration instructions of the package
inserts to optimize therapeutic benefits of the drug (92,93).
   It has been demonstrated that various modified-release formulations of the same drug
could exhibit different food effects. Some examples are theophylline and nifedipine
modified-release formulations (refer to labels for Theo-24 and Uniphyl, labels for Adalat
CC and Procardia) (83). When new modified-release formulations are developed with the
intention of switchability, it is critical to demonstrate bioequivalence under both fed and
fasted conditions.

4.3. Regulatory Studies Under Fed Conditions
   Concomitant food and drug intake could result in clinically significant effects that may
warrant appropriate study design considerations in the clinical trials. Information on food
administration in relation to drug intake also serves to optimize efficacy and safety once
drugs are approved, by providing important and useful directions to patients regarding
dosage and administration in package inserts. The FDA recommends that food-effect
bioavailability studies be conducted for all new drugs and drug products during the
Investigational New Drug (IND) period. The purpose of the study is to assess the effects
of food on the rate and extent of absorption of a drug when the drug product is adminis-
tered shortly after a meal as compared to administration under fasting conditions.
   When generic equivalents of new drugs are developed, the manufacturer is required
to submit an Abbreviated New Drug Application (ANDA). The FDA requires demonstra-
tion of switchability between the ANDA and the reference-listed drug (RLD). The
bioequivalence studies in support of switchability are recommended under both fasted
and fed states, with a few exceptions.

4.4. The Food-Effect Bioavailability and Fed Bioequivalence Studies
   Study design variables are central to the outcome of a food-effect bioavailability study.
Food effects on bioavailability are generally greatest when the drug product is adminis-
tered shortly after a meal is ingested. Nutrient and caloric contents of the meal, meal
volume, and meal temperature can cause physiological changes in the GI tract in a way
that affects drug-product transit time, lumenal dissolution, drug permeability, and sys-
temic availability. In general, meals that are high in total calories and fat content are more
Chapter 7 / Drug Absorption With Food                                                      145

likely to affect the GI physiology and thereby result in a larger effect on the bioavailability
of a drug substance or drug product. A survey of food-effect studies in NDAs for imme-
diate-release and modified-release products reviewed by FDA (survey conducted during
1991–1992 for drugs reviewed over the past 5–10 yr) revealed that important study
design variables were not consistent in these studies and yet package inserts were not
reflective of these irregularities. The FDA was also aware that the meal recommended for
the food-effect bioavailability studies was of a higher caloric content than the fed
bioequivalence study meal. These findings provided the impetus for harmonization
through a formal guidance development from the regulatory agency addressing study
design issues, data analysis, and labeling for studies under fed conditions.
   The FDA published a guidance for industry in January 2003 (94) that provides recom-
mendations on when food-effect bioavailability studies should be conducted as part of
INDs and NDAs and when fed bioequivalence studies should be conducted as part of
ANDAs. This guidance applies to both immediate-release and modified-release drug
products and provides recommendations for food-effect bioavailability and fed
bioequivalence study designs, data analysis, and product labeling.
   For INDs and NDAs, the guidance recommends that a food-effect bioavailability
study be conducted for all new chemical entities during the IND period. These studies
should be conducted early in the drug development process to guide and select formula-
tions for further development. Food-effect bioavailability information should be avail-
able to design clinical safety and efficacy studies and to provide information for
appropriate sections of product labels such as the ones entitled “Clinical Pharmacology”
and “Dosage and Administration.”
   For ANDAs, in addition to a bioequivalence study under fasting conditions comparing
the ANDA formulation to the RLD, a bioequivalence study under fed conditions is also
recommended for all orally administered immediate-release drug products with the follow-
ing exceptions: (a) when both test product and RLD are rapidly dissolving, have similar
dissolution profiles, and contain a drug substance with high solubility and high permeabil-
ity (BCS Class I), or (b) when the “Dosage and Administration” section of the RLD label
states that the product should be taken only on an empty stomach, or (c) when the RLD label
does not make any statements about the effect of food on absorption or administration.
   The guidance recommends that food-effect bioavailability for NDAs and fed
bioequivalence studies for ANDAs be performed for all modified-release dosage forms.
This section provides general considerations for designing food-effect bioavailability
and fed bioequivalence studies. Sponsors may choose to use alternative study designs
with scientific rationale and justification. They may also consider additional studies for
a better understanding of the drug product and to provide optimal labeling statements for
dosage and administration (e.g., different meals and different times of drug intake in
relation to meals). In studying modified-release dosage forms, consideration should be
given to the possibility that coadministration with food can result in dose dumping,
creating a potential safety risk for the study subjects.
146                                                 Part III / Influence of Food or Nutrients General Design. The guidance recommends a randomized, balanced, single-
dose, two-treatment (fed vs fasting), two-period, two-sequence crossover design for
studying the effects of food on the bioavailability of either an immediate-release or a
modified-release drug product. The formulation to be tested should be administered on
an empty stomach (fasting condition) in one period and following a test meal (fed con-
dition) in the other period. A similar, two-treatment, two-period, two-sequence crossover
design is recommend for a fed bioequivalence study except that the treatments should
consist of both test and reference formulations administered following a test meal (fed
condition). An adequate washout period should separate the two treatments in food-effect
bioavailability and fed bioequivalence studies. Subject Selection. Both food-effect bioavailability and fed bioequivalence
studies can be carried out in healthy volunteers drawn from the general population.
Studies in the patient population are also appropriate if safety concerns preclude the
enrollment of healthy subjects. A sufficient number of subjects should complete the study
to achieve adequate power for a statistical assessment of food effects on bioavailability
to claim an absence of food effect, or to claim bioequivalence in a fed bioequivalence
study. A minimum of 12 subjects should complete the food-effect bioavailability and fed
bioequivalence studies. Dosage Strength. In general, the highest strength of a drug product intended
to be marketed should be tested in food-effect bioavailability and fed bioequivalence
studies. In some cases, clinical safety concerns can prevent the use of the highest strength
and warrant the use of lower strengths of the dosage form. For products with multiple
strengths in ANDAs, if a fed bioequivalence study has been performed on the highest
strength, bioequivalence determination of one or more lower strengths can be waived
based on dissolution profile comparisons (90). Test Meal. In evaluating the exposure changes of new drugs (INDs/NDAs)
owing to food intake, the FDA seeks information on the “worst-case scenario” (i.e., the
largest food effect likely resulting from coadministration of drugs with meals). This
information is evaluated in the landscape of safety and efficacy of the drug and appro-
priate directions for use are incorporated in clinical trials and once the drug is approved
these directions are provided in the labeling. Additional studies may be conducted if
deemed useful. The FDA recommends that the fed bioequivalence study for ANDAs be
conducted with a meal likely to provide maximal GI perturbation, as well.
   The FDA recommends a high-fat (approx 50% of total caloric content of the meal) and
high-calorie (approx 800 to 1000 calories) meal for food-effect bioavailability and fed
bioequivalence studies. This test meal should derive approx 150, 250, and 500–600
calories from protein, carbohydrate, and fat, respectively. An example test meal would
be two eggs fried in butter, two strips of bacon, two slices of toast with butter, 4 ounces
of hash brown potatoes and 8 ounces of whole milk. Substitutions in this test meal can
be made as long as the meal provides a similar amount of calories from protein, carbo-
hydrate, and fat and has comparable meal volume and viscosity. In NDAs, it is recognized
that a sponsor can choose to conduct food-effect bioavailability studies using meals with
different combinations of fats, carbohydrates, and proteins for exploratory or label pur-
poses. However, one of the meals for the food-effect bioavailability studies should be the
high-fat, high-calorie test meal just described.
Chapter 7 / Drug Absorption With Food                                                       147 Administration.
   Fasted Treatments: Following an overnight fast of at least 10 h, subjects should be
   administered the drug product with 240 mL (8 fluid ounces) of water. No food should be
   allowed for at least 4 h post-dose. Water can be allowed as desired except for 1 h before and
   after drug administration. Subjects should receive standardized meals scheduled at the
   same time in each period of the study.
     Fed Treatments: Following an overnight fast of at least 10 h, subjects should start the
     recommended meal 30 min prior to administration of the drug product. Study subjects
     should eat this meal in 30 min or less; however, the drug product should be administered
     30 min after start of the meal. The drug product should be administered with 240 mL
     (8 fluid ounces) of water. No food should be allowed for at least 4 h post-dose. Water
     can be allowed as desired except for 1 h before and after drug administration. Subjects
     should receive standardized meals scheduled at the same time in each period of the study. Sample Collection. For both fasted and fed treatment periods, timed samples
in biological fluid, usually plasma, should be collected from the subjects to permit char-
acterization of the complete shape of the plasma concentration-time profile for the parent
drug. It may be advisable to measure other moieties in the plasma, such as active metabo-
lites (90). Data Analysis. Food-effect bioavailability studies may be exploratory and
descriptive, or a sponsor may want to use a food-effect bioavailability study to make a
label claim. The following exposure measures and pharmacokinetic parameters should
be obtained from the resulting concentration-time curves for the test and reference prod-
ucts in food-effect bioavailability and fed bioequivalence studies:
    Total exposure or area under the concentration-time curve (AUC0-inf, AUC0-t)
    Peak exposure (Cmax)
    Time to peak exposure (Tmax)
    Lag-time (tlag) for modified-release products, if present
    Terminal elimination half-life (t1⁄2 )
    Other relevant pharmacokinetic parameters
   An equivalence approach is recommended for food-effect bioavailability (to make a
claim of no food effects) and fed bioequivalence studies, analyzing data using an average
criterion for AUC and Cmax. Log-transformation of exposure measurements (AUC and
Cmax) prior to analysis is recommended. The 90% confidence interval for the ratio of
population geometric means between test and reference products should be provided for
AUC0-inf, AUC0-t, and Cmax (95). For IND or NDA food-effect bioavailability studies, the
fasted treatment serves as the reference. For ANDA fed bioequivalence studies, the RLD
administered under fed condition serves as the reference treatment.

   The results of food effect on drug exposure from food-effect bioavailability studies
should be evaluated for clinical relevance and appropriately described in package inserts.
   For an NDA, if the 90% confidence interval for the ratio of population geometric
means between fed and fasted treatments, based on log-transformed data, is not contained
in the equivalence limits of 80–125% for either AUC0-inf (AUC0-t when appropriate) or
148                                                   Part III / Influence of Food or Nutrients

Cmax, an absence of food effect on bioavailability is not established. In these situations,
the sponsor should provide specific recommendations on the clinical significance of the
food effect based on what is known from the total clinical database about dose–response
(exposure–response) and/or pharmacokinetic–pharmacodynamic relationships of the drug
under study. The sponsor should also indicate the clinical relevance of any difference in
Tmax and tlag. The results of the food-effect bioavailability study should be reported
factually in the “Clinical Pharmacology” section of the labeling and should form the basis
for making label recommendations (e.g., take only on an empty stomach) in the “Dosage
and Administration” section of the labeling. When important, other sections of the label
may include pertinent information about interactions with meals. The following are two
examples of general language for the package insert:
 1. A food-effect study involving administration of [the drug product] to healthy volunteers
    under fasting conditions and with a high-fat meal indicated that the Cmax and AUC were
    increased 57% and 45%, respectively, under fed conditions. This increase in exposure
    can be clinically significant, and therefore [the drug] should be taken only on an empty
    stomach (1 hour before or 2 hours after a meal).
 2. A food-effect study involving administration of [the drug product] to healthy volunteers
    under fasting conditions and with a high-fat meal indicated that the Cmax was decreased
    15% while the AUC remained unchanged. This decrease in exposure is not clinically
    significant, and therefore [the drug] could be taken without regard to meals.
   An absence of food effect on bioavailability is indicated when the 90% confidence
interval for the ratio of population geometric means between fed and fasted treatments,
based on log-transformed data, is contained in the equivalence limits of 80–125% for
AUC0-inf (AUC0-t when appropriate) and Cmax. In this case, a sponsor can make a specific
claim in the “Clinical Pharmacology” or “Dosage and Administration” section of the
label that no food effect on bioavailability is expected provided that the Tmax differences
between the fasted and fed treatments are not clinically relevant. The following is an
example of language for the package insert:
 1. The Cmax and AUC data from a food-effect study involving administration of [the drug
    product] to healthy volunteers under fasting conditions and with a high-fat meal indicated
    that exposure to the drug is not affected by food. Therefore, [the drug product] may be
    taken without regard to meals.
   For an ANDA, bioequivalence of a test product to the RLD product under fed condi-
tions is met with the following criteria. When the 90% confidence interval for the ratio
of population geometric means between the test and RLD product, based on log-trans-
formed data, is contained in the bioequivalence limits of 80–125% for AUC and Cmax.
Although no criterion applies to Tmax, the Tmax values for the test and reference products
are expected to be comparable based on clinical relevance.
   Historically, food-effect bioavailability studies have generated useful information on
optimal dosing instructions for patients with regard to meals. The examples described in
Tables 4–10 demonstrate the significance and utility of meal types, meal timing, and
other general information on drug intake with meals. Note that these examples are some
relevant excerpts from some approved labels; for complete information, refer to the
respective package inserts.
Chapter 7 / Drug Absorption With Food                                                   149

          Table 4
          Videx Labeling Information
          VIDEX (didanosine) Chewable/Dispersible Buffered Tablets
          VIDEX (didanosine) Buffered Powder for Oral Solution
          VIDEX (didanosine) Pediatric Powder for Oral Solution
          All VIDEX formulations should be administered on an empty stomach,
          at least 30 minutes before or 2 hours after eating.

  Table 5
  Fosamax Labeling Information
  FOSAMAX (alendronate sodium) Tablets
  FOSAMAX must be taken at least one-half hour before the first food, beverage, or
  medication of the day with plain water only. Other beverages (including mineral water),
  food, and some medications are likely to reduce the absorption of FOSAMAX. Waiting
  less than 30 minutes, or taking FOSAMAX with food, beverages (other than plain water)
  or other medications will lessen the effect of FOSAMAX by decreasing its absorption
  into the body.

  Table 6
  Retrovir Labeling Information
  RETROVIR (zidovudine)Tablets
  RETROVIR (zidovudine) Capsules
  RETROVIR (zidovudine) Syrup
  Effect of Food on Absorption: RETROVIR may be administered with or without food.
  The extent of zidovudine absorption (AUC) was similar when a single dose of zidovudine
  was administered with food.
  Adults: The recommended oral dose of RETROVIR is 600 mg per day in divided doses
  in combination with other antiretroviral agents.

  Table 7
  Mepron Labeling Information
  MEPRON (atovaquone) Suspension
  Dosage: Prevention of PCP: Adults and Adolescents (13 to 16 Years): The recommended
  oral dose is 1500 mg (10 mL) once daily administered with a meal.
  Treatment of Mild-to-Moderate PCP: Adults and Adolescents (13 to 16 Years): The
  recommended oral dose is 750 mg (5 mL) administered with meals twice daily for 21
  days (total daily dose 1500 mg).
  Note: Failure to administer MEPRON Suspension with meals may result in lower plasma
  atovaquone concentrations and may limit response to therapy.
150                                                        Part III / Influence of Food or Nutrients

        Table 8
        Plendil Labeling Information
        PLENDIL (Felodipine) Extended-Release Tablets
        PLENDIL should regularly be taken either without food or with a light meal.
        PLENDIL should be swallowed whole and not crushed or chewed.

       Table 9
       Cognex Labeling Information
       COGNEX (Tacrine Hydrochloride) Capsules
       Cognex should be taken between meals whenever possible; however, if minor
       GI upset occurs, Cognex may be taken with meals to improve tolerability.
       Taking Cognex with meals can be expected to reduce plasma levels approxi-
       mately 30% to 40%.

                   Table 10
                   Proscar Labeling Information
                   PROSCAR (Finasteride) Tablets
                   PROSCAR may be administered with or without meals.

    Food-effect bioavailability studies provide insight into the exposure changes resulting
from concomitant intake of drugs and meals. Exposure-response relationships translate
these changes into clinical relevance, and guide clinical trial designs. This information
also supports dosage and administration instructions for patients once drugs are approved,
by providing directions in the package inserts on whether or not the drug could be taken with
meals. Interactions with specific foods (e.g., grapefruit juice) and nutrients may need to
be studied separately and are generally based on theoretical expectations of physico-
chemical or physiological basis for interactions with specific drugs. Patients are more
informed and concerned about drug–food interactions than ever before. Health care
professionals must be aware of the potential for such interactions to provide patients with
optimum oral drug therapy and to serve as a resource of drug information. The evolving
literature and package inserts can offer information to help manage patients.

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Chapter 8 / Specific Foods and Non-Nutritive Components                                   155

      8          Effects of Specific Foods
                 and Non-Nutritive Dietary
                 Components on Drug Metabolism

                 Karl E. Anderson

   This chapter reviews the effects that specific components of foods have on the metabo-
lism and actions of drugs in humans. The review focuses on examples of such interactions
that are presently known, but it is not all-inclusive. Additional interactions are described
in more detail in the chapter references.
   Effects of diet on pharmacokinetics are most important clinically for drugs that have
a narrow therapeutic window or index, and when the effect of a drug closely reflects its
plasma concentration. For such drugs, a diet-induced change in kinetics may, at any given
dosage level, alter plasma drug levels sufficiently to render the drug either ineffective or
toxic. In contrast, a change in drug metabolism for a drug with a broad therapeutic
window is less likely to have an effect on efficacy or safety. Attention to food–drug
interactions is considered important by the Joint Commission on Accreditation of
Healthcare Organizations (JCAHO), which is an indication of their clinical relevance (1).

2.1. Studies in Healthy Subjects and Observations in Patients
   Some drug–nutrient interactions (DNIs) have been recognized in patients undergoing
treatment for medical or psychiatric conditions. However, many clinically relevant DNIs
are difficult to recognize and study in patients because effects of diet on drug metabolism
may not be recognized, and may be attributed to other causes. Observations in patients
are also likely to be confounded by underlying illness, organ dysfunction, alterations in
fluid distribution, and exposure to multiple drugs. These concurrent confounding factors
can limit recognition of effects of diet. Moreover, dietary variations are often complex
and difficult to accurately determine in the clinical setting. Therefore, it is not surprising
that many such effects have been first recognized in studies of healthy subjects under
controlled experimental conditions. Studies in healthy subjects have also been important
for documenting and explaining the underlying mechanisms for such interactions. Even

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
156                                                 Part III / Influence of Food or Nutrients

if it remains difficult to recognize specific occurrences of such interactions in individual
patients, and such interactions are demonstrated mostly in healthy subjects, it is important
to warn patients and health professionals of their potential for complicating drug therapy
in clinical practice.

2.2. Drug Metabolic Pathways Likely To Be Affected by Diet
   Foods—and vegetables in particular—are a complex mixture of chemicals, many of
which are not recognized to provide nutritional value to the host. Nutritive components
and non-nutritive chemicals may have unwanted effects on metabolic processes, includ-
ing pathways of drug metabolism. Effects of some dietary substances resemble the more
easily recognized effects of certain drugs on the metabolism of other drugs. Indeed, many
drugs are derived from chemicals in plants. Therefore, it is not surprising that DNIs and
drug–drug interactions have many common features and can be of similar magnitude (2).
   The cytochrome P450 (CYP) enzymes found in the endoplasmic reticulum of cells in
the liver and intestinal mucosa are important for many drug–drug interactions because
many drugs can either inhibit or induce one or more of these enzymes and thereby greatly
influence the metabolism and clearance of other drugs. CYP enzymes are a large family
of hemoproteins that oxidize both exogenous and endogenous chemicals. The enzyme
reactions require both molecular oxygen and nicotinamide adenine dinucleotide phos-
phate. CYP-catalyzed reactions are termed mixed function oxidase or monooxygenase
reactions because only one atom of the oxygen molecule is utilized for oxidizing the
substrate, whereas the other oxygen atom reacts with protons to form water (3).
   Diets and their components may, like drugs, induce or inhibit these important enzymes.
Effects of diet on drugs that are metabolized by CYP enzymes have been most studied in
humans (3). Effects on conjugating enzymes and P-glycoprotein (P-gp) are also impor-
tant for some drugs and dietary factors. It is likely that many unknown effects of diet on
drug metabolism remain to be discovered both by clinical observations and in careful
metabolic studies. Additional studies are needed in the elderly and in patients with spe-
cific diseases that can affect diet and nutritional status (4).

   Effects of diet and nutrition were initially recognized in animals, particularly rodents
(5,6). Some observations in animals have predicted effects of diet observed later in
humans (3). But it is difficult to extrapolate the conclusions of animal studies to humans
because of the major differences between species in CYP and other drug-metabolizing
enzymes. Additionally, differences in CYP enzymes between males and females are
prominent in rodents and much less important in humans (7).
   In addition to being more relevant, studies in humans have other advantages. Human
subjects are more compliant with dietary changes especially during short-term studies
in supervised settings, making it possible to make a specific change in dietary compo-
sition without altering other components and total energy intake. Therefore, it is possible
to observe effects of a change in diet without a confounding effect of a change in the total
amount of energy consumed. Such studies are quite difficult in animals, without resorting
to study design strategies such as pair feeding.
   Effects of diet have been studied for only a small proportion of the drugs available for
clinical usage. Many drugs are metabolized by several different CYP enzymes and also
Chapter 8 / Specific Foods and Non-Nutritive Components                                157

by conjugating enzymes. Other pathways, such as transport by P-gp, may also be influ-
enced by diet. Although effects of diet components on the metabolism of some drugs are
well documented, it is not always evident which specific enzyme isoform is affected, and
it remains difficult to extrapolate from one drug substrate to another.

3.1. Effects of Dietary Protein, Carbohydrate, and Fat
   The first recognized effect of diet on human drug metabolism was seen in crossover
studies in healthy male subjects. Dietary protein and carbohydrates were exchanged
sequentially, while keeping fat and total energy constant (8,9). Metabolic clearances of
both antipyrine and theophylline were more rapid, and plasma levels of these drugs
declined more rapidly, during the high-protein diet. These drugs were chosen for study
because their clearances are dependent on metabolic tranformations by CYP enzymes in
the liver. The metabolism of these drugs may especially reflect activity of hepatic
CYP1A2 (7).
   In further studies, the addition of a pure protein supplement (100 g of sodium caseinate
each day for 2 wk) to a calculated well-balanced diet in two subjects increased the rates
of metabolism of antipyrine and theophylline, whereas in two other subjects, a supple-
ment of carbohydrate (200 g of sucrose daily for 2 wk) had the opposite effect (9).
Increasing the protein content of the diet also accelerated the metabolism of propranolol
(10) and perhaps aminopyrine and caffeine (11). An effect of protein on theophylline and
propranolol clearance has been shown to occur in both women and men (10).
   Further studies compared the effects of high-carbohydrate, high-fat, and high-protein
diets on drug metabolism (12). Composition of the three diets permitted observations on
the effects of the isocaloric substitution of fat for carbohydrate while keeping protein
constant at 10% of total calories, and the substitution of dietary protein for fat while
keeping carbohydrate constant at 20% of total calories in the six healthy male subjects.
As shown in Table 1, metabolic clearances for antipyrine and theophylline were greater
during the high-protein dietary period than during the other two diets, as in previous
studies, but there were no differences in the drug clearances between the high-fat and
high-carbohydrate dietary periods. The conclusion was that the substitution of protein for
either fat or carbohydrate can increase drug oxidation rates, whereas exchanging carbo-
hydrate and fat has no major effect (12).
   The lack of an effect of carbohydrate and fat, including both saturated and unsaturated
fats, were confirmed in an additional study in nine normal males (12). Large isocaloric
exchanges of carbohydrate for either unsaturated fat (corn oil) or saturated fat (butter)
were accomplished while maintaining dietary protein constant at 15% of total calories.
No significant changes in the metabolism of antipyrine and theophylline were observed
(12). Others have confirmed that substituting saturated and unsaturated fat in the diet of
normal subjects has no effect on the metabolism of antipyrine (13). Therefore, isocaloric
exchanges of saturated fat, unsaturated fat, and carbohydrate do not appear to influence
the metabolism of at least some substrates for CYP enzymes in humans. Changes in
dietary fat can influence hepatic drug oxidations in animals (5). It remains possible that
some CYP enzymes or other enzymes important in drug metabolism may be influenced
by dietary fat.
   Thus, protein content of the diet appears to be more important for regulating oxidative
drug metabolism in humans than carbohydrate or fat. Moreover, studies at different
158                                                              Part III / Influence of Food or Nutrients

Table 1
Drug Metabolism During Diets High in Protein, Carbohydrate, or Fat
                                   Diet Composition                                 Clearance
                      Protein         Fat      Carbohydrate                Antipyrine      Theophylline
        Diet                                 (%)                                   (mL kg–1 min–1)
High carbohydrate         10            10                80              0.57     0.02          0.76    0.06
High fat                  10            70                20              0.59     0.02          0.74    0.04
High protein              50            30                20              0.71     0.05*†        0.98    0.08¶
   Each calculated diet was consumed in the order shown by six normal male subjects, and antipyrine
metabolism was studied on day 10 and theophylline metabolism on day 14 of each dietary period. Clearance
values (means ± SE) during the high-protein dietary period were significantly different from the high
carbohydrate dietary period (*p < 0.005), and the high fat dietary period (†p < 0.01, ¶ p < 0.02, paired t-test).
   From ref. 12.

intakes of total calories indicate that dietary protein can influence drug-oxidation rates
at levels of energy intake other than that needed to maintain body weight (14). Protein
content of the diet may influence drug metabolism in patients with cirrhosis (15) as well
as other clinical settings. For example, in hospitalized children with asthma, clearance of
theophylline was greater during a high-protein diet than during two diets lower in protein
content. Theophylline levels were higher and wheezing episodes and requirements for
additional medications less frequent during a low-protein diet (Table 2) (16). In adults
with obstructive pulmonary disease, theophylline concentrations were lower during a
high-protein diet than during a high-carbohydrate diet (17).
   The mechanism whereby dietary protein accelerates drug oxidation in humans is not
established. Although human studies have mostly involved solid-food diets, it is unlikely
that non-nutritive components of the diet were responsible for the effects ascribed to
protein. The effects of feeding high-protein diets have been observed by different inves-
tigators that presumably were not uniform in terms of the solid foods in the experimental
diets. Moreover, a protein supplement had the same effect as a high-protein diet in healthy
subjects (9). Effects of dietary protein on drug metabolism in humans were corroborated
by earlier studies of high-protein diets in rodents, although the results in rodents are more
complex owing to marked differences between males and females that are not found in
humans. Because the diets for the human studies were adequate in all essential nutrients,
the substantial effects on drug metabolism were not a result of the correction of deficien-
cies in protein or other nutrients. Impaired gastrointestinal (GI) absorption or altered
distribution after absorption of the test drugs has also not been a factor in such studies (18).
   The mechanisms of protein effects on CYP enzymes in laboratory animals are also not
known (3). High-protein intakes augment hepatic microsomal CYP content, liver weight,
and mitotic indices in rodents (5,19). These effects are reminiscent of the inducing effects
of phenobarbital. Certain amino acids such as tryptophan and oxidized sulfur may in-
crease liver-protein synthesis and induce the mixed-function oxidase system in labora-
tory animals and in liver cell cultures (20–24).
   The metabolism of steroid hormones occurs primarily in the liver and by CYP
enzymes, microsomal reductases, and conjugating enzymes (25). Dietary effects on
these enzymes might also be expected. Indeed, an increase in the protein-to-carbohydrate
Chapter 8 / Specific Foods and Non-Nutritive Components                                               159

Table 2
Theophylline Clearances and Serum Concentrations and the Total Number of Wheezing
Episodes Occurring in Children With Asthma During Diets Differing in Protein Content
                           Diet Composition                              State Serum
                      Protein Fat Carbohydrate             Clearance     Concentration Wheezing
        Diet                      (%)                     (L kg–1 min–1)    (mg mL–1)  Episodes
Normal            6–8            35       57–60          0.059     0.015      14.04     3.97        22
High protein     14–20           20       60–66          0.071     0.019*     10.66     3.43        17
High carbohydrate 2–3            20       77–78          0.048     0.016*     17.24     5.68         9
   After-steady state serum concentrations of theophylline of 10–20 µg/mL were achieved, children (age
7–14 yr) were fed the three test diets in the order shown, each for 12 d (with 2 d on a usual diet between
each of the test diets). Values for theophylline clearance and concentration are means S.D.
   *Significantly different from results obtained during the normal diet (*p < 0.001, paired t-test). (From

refs. 16,139.)

ratio of the diet can increase estrogen 2-hydroxylation (26) and decrease androgen
5 -reduction in healthy subjects (27). The same dietary change may alter the plasma
concentrations of testosterone and cortisol in a reciprocal fashion and produce parallel
changes in the binding globulins for these steroids (28). These effects mimic those induced
by phenobarbital in humans (29).
   Dietary protein can also alter the disposition of drugs that are cleared primarily by the
kidneys, by influencing renal plasma flow, creatinine clearance, and renal tubular trans-
port (30, 31). Renal tubular transport of basic drugs or drug metabolites may be especially
reduced. For example, allopurinol is readily absorbed from the GI tract and rapidly
converted by hepatic xanthine oxidase or aldehyde oxidase to its major metabolite,
oxypurinol, which is then excreted largely unchanged in the urine. Berlinger et al. (1985)
studied the pharmacokinetics of allopurinol in normal subjects during consumption of a
high protein and low protein diets. A marked increase in area under the curve for
oxypurinol and a decrease in renal clearance of this metabolite were demonstrated in
healthy subjects during a low protein diet compared to a high protein diet. It was postu-
lated that protein restriction produced an increase in the net tubular reabsorption of
oxypurinol (32). Therefore, in some patients treated with allopurinol, dietary restriction
may enhance the retention of oxypurinol and increase the likelihood of adverse effects.
   Protein and other specific food components in the diet can also enhance or interfere
with the absorption of some drugs. For example, theophylline absorption has been
reported to be faster after a high-protein meal than after a high-carbohydrate or high-
fat meal (32a). The buffering capacity of protein is greater than for carbohydrate and fat.
Therefore, a high-protein diet may enhance the bioavailability of acid-labile drugs to a
greater extent than a lower protein diet.
   A dietary component can influence delivery of a drug to its central site of action. For
example, a low-protein diet can benefit patients with Parkinson’s disease during treat-
ment with levodopa by reducing unpredictable fluctuations in response (the “on–off”
phenomenon) (33–35). Levodopa absorption and blood levels are not affected by protein
160                                                   Part III / Influence of Food or Nutrients

restriction, indicating that the effect occurs at a more central level (36,37). Rather, a high-
protein intake provides amino acids, especially large neutral amino acids, which inhibit
the transport of levodopa across the blood–brain barrier (BBB) by the aromatic amino
acid transporter (38). This leads to reduced brain dopamine formation from exogenous
levodopa (39). A protein redistribution diet, with protein restriction during the day and
unrestricted intake near bedtime was found to be beneficial in clinical studies (36,40–42).
But deficiencies may develop if intakes of protein or other nutrients are marginal prior
to the dietary change (43). A diet balanced in protein and carbohydrate has also been
advocated (44). As described later, efficacy of levodopa can also be affected by vitamin
B6 intake.

3.2. Cruciferous Vegetables
   Cruciferous vegetables and alfalfa meal, when added to the diet of laboratory animals,
were found to markedly induce chemical oxidation (45–47). The inducing effects of
cruciferous vegetables were accounted for primarily by indoles, including indole-3-carbinol
and indole-3-acetonitrile (48). Certain strains of cabbage and Brussels sprouts are particu-
larly rich in these inducing substances. These vegetables and indoles have effects on the
metabolism of environmental carcinogens such as aflatoxin B1 and binding of their
metabolites to DNA (49–51).
   These observations led to studies in humans. Drug oxidation and conjugation have
been studied in normal subjects on calculated diets. Brussels sprouts and cabbage were
substituted for other vegetables shown not to enhance mixed function oxidation in ani-
mals. The cruciferous vegetables significantly enhanced the oxidative metabolism of
antipyrine and phenacetin (Tables 3 and 4) (46) and conjugation of acetaminophen (52).
   Cruciferous vegetables can complicate the use of warfarin and other coumarin antico-
agulants. The vitamin K content of these vegetables and other foods can antagonize the
anticoagulant effects of these drugs. Furthermore, a diet rich in Brussels sprouts can
enhance the elimination rate of warfarin (53). Coumarins in some herbal teas may
enhance effects of coumarin anticoagulants (1). Maintaining a reasonably constant
intake of vitamin K and foods containing other substances that can influence the metabo-
lism and effects of these anticoagulant drugs can help to keep the prothrombin time
within the desired therapeutic range during long-term anticoagulation.

3.3. Grapefruit Juice
   The effect of grapefruit juice on metabolism of drugs that are metabolized by CYP3A4
has become perhaps the best-known DNI, and is discussed in detail in the next chapter.
The initial serendipitous observation of this effect occurred in 1989 when grapefruit juice
was used as a vehicle in a study of the effects of alcohol on felodipine metabolism (53a).
It was noted that grapefruit juice decreased the oral clearance of this calcium channel
blocker, and enhanced the area under the plasma concentration vs time curve. Because
the bioavailability of the drug was increased, the systemic exposure and pharmacody-
namic effects increased. Subsequently, interactions between a variety of drugs and grape-
fruit juice were studied (54) (see Chapter 9).
   Grapefruit juice contains furanocoumarins and other substances that can inhibit
CYP3A and to some extent other CYP isoforms. CYP3A inhibition by grapefruit juice
occurs only in the small intestine. As a result, drugs that are substantially metabolized by
Chapter 8 / Specific Foods and Non-Nutritive Components                                                  161

Table 3
Effects of Dietary Brussels Sprouts and Cabbage on Antipyrine Metabolism in Healthy Subjects
                                                                   Antipyrine Clearance
           Diet                                                           (L h–1)
Control (first time)                                                    3.09    0.31
Brussels sprouts and cabbage                                            3.44    0.32*
Control (second time)                                                   2.98    0.33
   Each diet was fed to 10 healthy subjects in the sequence shown. Values are means S.E.
   *Significantly different from both control diet periods (p < 0.002, paired t-test). (From ref. 46.)

Table 4
Effects of Dietary Brussels Sprouts and Cabbage on Phenacetin Metabolism in Healthy Subjects
                                            Phenacetin AUC
             Diet                             (µg h mL–1)
Control (first time)                          5283     1864
Brussels sprouts and cabbage                  2718     779*
Control (second time)                         4391     1506
   Diets were fed to 10 subjects in the order shown. Values for area under the plasma concentration vs time
curve (AUC) are means S.E. for 0–7 h.
   * Plasma phenacetin concentrations were significantly lower at 3, 4, 5, and 7 h and plasma levels of total
N-acetyl-p-aminophenol were significantly higher at 1, 2, and 7 h during the test diet period than during both
control diet periods (p < 0.05–0.001, paired t-test). (From ref. 46.)

CYP3A during absorption from the intestinal lumen are most notably affected by grape-
fruit juice. Drugs administered parenterally are not affected. Inhibition is both reversible
and irreversible. Recovery from irreversible inhibition requires synthesis of new enzyme,
and the limited information available suggests this may take up to 72 h after grapefruit
juice exposure (54). Inhibition by grapefruit juice is clinically important when drug
response closely reflects plasma concentration, as is the case for calcium channel blockers.
   Because this interaction occurs primarily with drugs that are subject to extensive first-
pass metabolism by CYP3A in the intestine, there are many drugs that are not affected.
As a result, it is often possible within a class of drugs to choose an alternative that is not
subject to inhibition by grapefruit juice, or to predict whether this interaction might occur
based on the known pharmacokinetic features and pathways of metabolism of a drug.
Examples of drug groups where such choices can be made include calcium channel
antagonists, -hydroxy- methylglutaryl-CoA reductase inhibitors, sedative-hypnotics
and anxiolytics, psychotropics, and antihistamines (54). However, it must be kept in mind
that inhibition of CYP3A4 may not be the only mechanism whereby grapefruit juice
affects drug metabolism. Drug transporters such as P-gp in enterocytes may also be
affected, and this mechanism may be more important than the CYP3A4 inhibition for
some drugs such as cyclosporin (54,55).
162                                                 Part III / Influence of Food or Nutrients

3.4. Herbs
   Herbs represent complex and incompletely characterized mixtures of chemicals. Their
effects on the metabolism and actions of drugs have received recent attention but remain
largely unexplored. Reports of possible herb–drug interactions are often incomplete.
Reviewers of this field have concluded that such interactions almost certainly occur and
may put patients at risk, but further studies are needed (56–59).
   Interactions of herbs with warfarin, for example, are in general poorly documented
(59). Bleeding has been reported when warfarin is combined with ginkgo (Ginkgo biloba)
(59). However, a controlled prospective study failed to confirm such an effect (60).
Examples of other herbs reported to interact with warfarin to cause bleeding include dong
quai (Angelica sinensis) (61) and danshen (Salvia miltiorrhiza) (62).
   St John’s wort (Hypericum perforatum) can cause induction of CYP3A4 and 2E1 (63),
possibly 2C9 and 1A2, and P-gp, and decrease the blood concentrations or effects of
drugs such as digoxin, theophylline, cyclosporin, protease inhibitors (e.g., indinavir and
nevirapine), coumarin-derived anticoagulants, amitriptyline, and oral contraceptives
(56,64–66). The inducing effect on CYP3A4 is greater in females than in males (63).
Serotonin syndrome has been noted in patients who take St. John’s wort along with
serotonin-reuptake inhibitors, nefazodone, or triptans (56,64,65). Garlic oil was found to
reduce CYP2E1 in healthy subjects (63).
   Ginseng has been reported to induce mania in patients taking antidepressants (56,67).
Heavy betel nut (Areca catechu) consumption may precipitate extrapyramidal side effects
with schizophrenic patients on neuroleptic drugs (68). Yohimbine (Pausinystalia yohimbe)
may increase risk of hypertension in patients taking tricyclic antidepressants (56). Liquo-
rice (Glycyrrhiza glabra) may potentiate oral and topical corticosteroids (56) and digi-
talis (69). Heavy intake of licorice products can be an inapparent cause of hypertension
that is resistant to drug therapy (70).
   Because herbal products in the United States are not subject to standardization and
regulation of quality, their content is often variable and uncertain. Many of the chemical
components of these plant products and their potentially significant effects on drug
disposition and action remain unknown. Therefore, it is widely recommended that
patients taking prescribed drugs should not take herbal remedies, unless authorized by
their physicians (56,65).
3.5. Methylxanthines
    Methylxanthines such as caffeine (1,3,7-trimethylxanthine) are common natural, non-
nutritive components of foods and especially beverages such as coffee and tea. Caffeine
is added to many popular carbonated beverages. Theophylline (1,3-dimethylxanthine) is
a drug used extensively as a bronchodilator in treating asthma and related pulmonary
    CYP enzymes extensively metabolize these and other methylxanthines. When ingested
regularly, these substances can also accumulate and influence drug metabolism. Effects on
drug metabolism are complex, and may involve saturation and inhibition as well as
induction of hepatic enzymes that metabolize methylxanthines and other drugs and chemi-
cals. For example, with repeated doses, theobromine (3,7-dimethylxanthine), a major
methylxanthine in chocolate, lowers its own metabolism by saturating or inhibiting
hepatic enzymes; but several days after the last repeated dose, induction of theobro-
Chapter 8 / Specific Foods and Non-Nutritive Components                                    163

mine hepatic metabolism can be demonstrated (71). Theobromine induction of its own
metabolism was shown to occur in rats as well (72). Theophylline also can induce its own
metabolism in humans (73). Studies in healthy subjects indicate that a pool of
methylxanthines derived from the diet may compete with theophylline for common
saturable metabolic pathways (74).
   Cola nuts, which are reported to contain 2.3% caffeine, are commonly chewed in
Africa and elsewhere for stimulant effects. Antipyrine half-life was prolonged by cola-
nut chewing in a cross-sectional study employing multiple regression analysis in Gambian
villagers (75). However, this effect was not seen in a controlled study in normal male
volunteers in the United States (76). This difference is not explained, but it is possible that
other nutritional factors influenced metabolism of the test drug antipyrine in the West
African study.
   An interaction between caffeine and clozapine, both of which are CYP1A2 substrates,
has been demonstrated in schizophrenic patients (77). In seven subjects on monotherapy,
clozapine concentrations were lower after they were changed to a caffeine-free diet for
5 d. Therefore, habitual caffeine intake can alter the metabolism of this drug. The findings
suggest that caffeine intake should be medically supervised and levels of clozapine
monitored in some schizophrenic patients (77).

3.6. Food Preparation
   Chemical changes in foods are induced during cooking at particularly high tempera-
tures, and the chemical products may be absorbed and then influence drug-metabolic
pathways. For example, charcoal broiling of meats leads to formation of polycyclic
aromatic hydrocarbons similar to those found in cigarette smoke. Polycyclic aro-
matic hydrocarbons in cigarette smoke probably account for enhanced drug-oxidation
rates in smokers (78).
   These chemicals are products of incomplete combustion, and are produced during
charcoal broiling when drippings contact the hot coals, and are then volatilized and
redeposited on the meat (79). Oral administration of such compounds to rats increases
benzo(a)pyrene hydroxylase activity in the intestine and liver. Moreover, feeding char-
coal-broiled beef induces intestinal metabolism of phenacetin in the rat (80).
   Charcoal-broiled beef can have substantial effects on the metabolism of drugs such as
phenacetin, theophylline, and antipyrine in healthy subjects (81–83). Pharmacokinetics
of these drugs were studied during periods of daily ingestion of standard portions of
hamburger (8 ounces) and steak (6 ounces) that were broiled over charcoal and fed twice
daily as part of a calculated test diet, and again during control diet periods, when alumi-
num foil was placed under the meat and drippings aspirated by hand to prevent their
falling onto the burning charcoal. Phenacetin plasma concentrations were markedly
reduced by consumption of charcoal-broiled beef, and the ratio of the major metabolite
of phenacetin, N-acetyl-p-aminophenol (acetaminophen) to phenacetin was increased
(Table 5) (81). Therefore, both charcoal-broiled beef and cigarette smoking enhance
phenacetin O-dealkylation in humans. In a separate study, clearance of antipyrine and
theophylline were increased by consumption of charcoal-broiled beef (82). Clinical
usage of phenacetin has been largely replaced by acetaminophen, which is metabolized
primarily by conjugation. Acetaminophen metabolism was not influenced by consump-
tion of charcoal-broiled beef (84).
164                                                            Part III / Influence of Food or Nutrients

      Table 5
      Effect of Charcoal-Broiled Beef on Phenacetin Metabolism in Healthy Subjects
                                                                 Phenacetin AUC
              Diet                                                (µg min mL–1)
      Control (first time)                                           170     40
      Charcoal-broiled beef                                           37     8*
      Control (second time)                                          174     53
         Each diet was consumed by nine subjects in the order shown. Values for area under the
      plasma concentration vs time curve (AUC) are means S.E. for 0–7 h.
         *Significantly different during the test diet than during control diet periods (p < 0.01, first
      time; p < 0.025, second time; paired t-test). (From ref. 81.)

3.7. Tyramine and Related Substances
   Hypertensive reactions may occur in patients taking monoamine oxidase inhibitors
(MAOIs) after ingestion of foods containing tyramine, such as some highly flavored
cheeses. These “tyramine reactions” or “cheese reactions” are among the best-known
DNIs (85). They began to be reported with use of the irreversible MAOIs from about
1961. By about 1965, the underlying mechanisms were understood to involve tyramine-
provoked hypertension, and fairly simple dietary precautions could be recommended
(86,87). However, fear of these sometimes severe reactions persisted, and greatly limited
the use of first generation, nonselective MAOIs as antidepressants, such as tranylcyprom-
ine, pargyline, phenelzine, selegiline, and isocarboxazide (85,86).
   Manifestations of these sudden and dramatic reactions may include hypertension with
palpitation, nausea, vomiting, and headache. The potentially life-threatening hyperten-
sive crises, which may occur within 1 h of ingestion of the tyramine-containing food, are
described as resembling the paroxysmal symptoms of pheochromocytomas, which are
neuroendocrine tumors that intermittently release catecholamines into the circulation (85).
   Tyramine and other phenylethylamines are formed from tyrosine owing to the actions
of bacterial and fungal tyrosine decarboxylase. Monoamine oxidase in the intestine and
liver normally oxidatively deaminates phenylethylamines that are absorbed from the
diet. When monoamine oxidase is inhibited in these tissues by a drug, dietary
phenylethylamines can be absorbed systemically and displace norepinephrine from stor-
age vesicles in the nervous system. Large amounts of this neurotransmitter are then
released into synapses, which can lead to severe acute hypertension, and additional
complications such as myocardial infarction and thrombotic or hemorrhagic stroke (1).
Paradoxically, the interaction between cheddar cheese and tranylcypromine was used to
therapeutic advantage in two patients with severe postural hypotension (88).
   Although highly flavored cheeses, such as cheddar, are most commonly associated
with this adverse drug interaction, other high-protein foods that have started to ferment
may also contain large amounts of tyramine or other phenylethylamines (1). These
include pickled herring, yeast preparations, broad beans, and certain wines (e.g., Chi-
Chapter 8 / Specific Foods and Non-Nutritive Components                                   165

anti) and beers (89,90), Amounts of these substances in foods and beers can vary greatly
from sample to sample. Tap lager beers prepared by bottom fermentation may contain
amounts of tyramine that are significant even for moderate levels of beer consumption,
and have been implicated in hypertensive reactions to MAOIs (89).
   Rates of absorption and delivery of dietary phenylethylamines to the systemic circu-
lation can be greatly affected by other foods in the meal. Iron deficiency is said to increase
susceptibility to these reactions. Concurrent sympathomimetic drugs may also exacer-
bate tyramine reactions. Reactions related to ingestion of broad beans (fava beans) may
be due in part to their content of dopa or its amine derivative dopamine (1).
   Other drugs with weak monoamine oxidase-inhibiting properties, such as furazolidine
(an antiprotozoal) and meperidine (a narcotic analgesic) have also been implicated in
tyramine reactions (1). Procarbazine has been reported to cause hypertension in patients
consuming tyramine-containing foods while taking this drug for Hodgkin’s disease (91).
Isoniazid (an antituberculosis drug) is a weak MAOI that may cause tyramine reactions
in combination with tricyclic antidepressants (92).
   Strategies to avoid tyramine reactions in patients taking MAOIs have included dietary
restrictions and development of new pharmaceutical products (93). Based on analysis of
phenylethylamine content of foods and case reports of diet-related hypertensive reac-
tions, rational guidelines for diet planning and counseling of patients on MAOI drug
regimens have been described. Some confidence in the safe use of these drugs may be
provided by beginning dietary counseling before drug therapy, keeping tyramine intake
below 5 mg, and recommending consumption of only fresh foods. Any food rich in
aromatic amino acids can become high in tyramine with aging, or when microbial con-
tamination is followed by prolonged storage or spoilage occurs (87). It has been recom-
mended that all tap (draft) beers should be avoided even at modest levels of consumption
(90). Dietary compliance should be monitored, and dietary restrictions continued 4 wk
after completion of drug therapy (87).
   Altering the route of drug administration has been explored. For example, a selegiline
transdermal system, when used for treating depression, apparently allows inhibition of
central nervous system monoamine oxidase type A (MAO-A) and monoamine oxidase
type B (MAO-B) enzymes while avoiding inhibition of intestinal and liver MAO-A
enzyme. Transdermal administration of this drug to adults with major depression was
reported to not significantly increase sensitivity to dietary tyramine (94).
   Pharmaceutical strategies of particular interest include combining MAOIs with tricy-
clic antidepressants and development of new selective and reversible MAOIs. Effective-
ness of such approaches can be assessed by the tyramine pressor test (93). Selegiline is
approved as adjunctive treatment of Parkinson’s disease using lower doses (e.g., 10 mg/d
by mouth) than is used for depression. When used in this manner, selegiline does not inhibit
intestinal and hepatic MAO-A, and is therefore a selective, irreversible cerebral MAO-B
inhibitor without significant risk of the tyramine reaction (95,96). However, this dose-
dependent selectivity is not absolute, and a few hypertensive reactions have been reported
even at the recommended doses for Parkinson’s disease, and there is some selectivity
retained at higher doses as well (97,98). Rapidly reversible MAO-A inhibitors, such as
moclobemide, a novel benzamide, are reported to carry less risk of a hypertensive reac-
tion and yet appear to be effective antidepressants (97,99), but with doses above 900
mg/d the risk of interaction with dietary tyramine may be significant (100).
166                                                  Part III / Influence of Food or Nutrients

3.8. Alcohol
   Adverse reactions develop soon after alcohol is consumed in patients treated with
tetraethylthiuram disulfide (disulfuram). For this reason, the drug has been used in alco-
hol treatment programs as an adjunctive means of encouraging abstinence. The unpleas-
ant manifestations of this food–drug interaction may include flushing, headache, nausea,
vomiting, weakness, vertigo, hypotension, blurred vision, and seizures. The drug inhibits
the enzyme aldehyde dehydrogenase, which oxidizes acetaldehyde that is derived from
alcohol. Cyanamide is a disulfiram-like drug that has been used for the management of
alcoholism in some countries such as Japan, but has been associated with adverse effects
on the liver (101). The disulfiram reaction has been reproduced using acetaldehyde, and
has therefore been termed the “acetaldehyde syndrome.” It can occur with ingestion of
foods cooked with wine, wine vinegar, or wine-containing desserts (102).
   Other drugs have been found to cause disulfuran-like reactions in association with
alcohol (1). These drugs, some of which are aldehyde dehydrogenase inhibitors, include
cyanamide, metronidazole, sulfonylureas (103), griseofulvin (104), procarbazine, some
cephalosporin antibiotics, and possibly ketoconazole (105). Some mushrooms contain
inhibitors of aldehyde dehydrogenase and may cause such reactions (106,107). Inhibitors
of this enzyme may be found in other foods, such as cabbage (108).
   The potential for metronidazole to cause a disulfiram-like reaction has been ques-
tioned, based on lack of convincing case reports or evidence for inhibition of hepatic
alcohol dehydrogenase (109,110). This drug may increase acetaldehyde production in
the colon, at least in rats (111).
   Cephalosporin antibiotics have differing effects on the liver alcohol dehydroge-
nase and circulating acetaldehyde levels (112,113). Those reported to cause disul-
firam-like reactions include cefoperazone, moxalactam, ceftriaxone, cefonicid, and
cefmetazole (114–116). Reactive metabolites rather than the parent drugs are thought to
be responsible for the enzyme inhibition (117). Drugs with an N-methyltetrazolethiol
side chain in the 3' position, and certain other side chains are particularly associated with
this reaction. Drugs with these structural features can also inhibit vitamin K epoxide
reductase and cause coagulopathies (hypoprothrombinemia and bleeding), particularly
in patients with vitamin K deficiency (114,118–121). Vitamin K administration can
prevent this drug-induced coagulopathy.
3.9. Vitamins
   A number of vitamin deficiencies alter hepatic mixed-function oxidations in labora-
tory animals (5,6,122). Therefore, it is likely that ingestion of vitamins may alter drug
metabolism in humans by correcting evident or subtle vitamin deficiencies in patients.
But there are few studies in humans, and the observations in animals are difficult to
translate to human populations owing to marked species differences in drug metabolism.
There is also some potential for large doses of vitamins to alter drug metabolism in
subjects without vitamin deficiencies.
   The effects of vitamin C have been most studied in humans. Several species, including
humans, guinea pigs, and other primates, as well as some strains of rats, are unable to
synthesize vitamin C, and therefore require small amounts in the diet. Interrelationships
between vitamin C and CYP enzymes were examined in some detail in early studies
(123). Depletion of this vitamin in the guinea pig and in a rat strain unable to synthesize
Chapter 8 / Specific Foods and Non-Nutritive Components                                   167

ascorbic acid impairs oxidative drug metabolism and reduces CYP and most associated
enzyme activities (124,125). Amounts of ascorbic acid required for optimal induction of
CYP by exogenous chemicals (e.g., polychlorinated biphenyls) exceed the amounts re-
quired to maintain induced levels of mixed-function oxidase activities (125).
   Observations in a few patient populations suggest that vitamin C deficiency impairs
drug metabolism in humans. For example, antipyrine half-lives were longer in liver
disease patients with low leukocyte ascorbate levels than in patients with higher ascor-
bate levels (126). Ascorbic acid supplementation of elderly patients (127) and diabetics
(128) with low initial leukocyte or serum ascorbate levels resulted in shortening of
antipyrine half-lives. It is possible that additional nutritional deficiencies contributed to
impaired drug metabolism in these studies.
   Studies in healthy subjects have not found a substantial effect of vitamin C deficiency.
For example, subclinical vitamin C deficiency of short duration in five male volunteers
had no significant effect on antipyrine metabolism (129). In 10 elderly subjects who
underwent ascorbate depletion for 4 wk, no significant change in caffeine metabolism
was reported (130). It is possible that effects on drug metabolism occur in humans only
with more severe deficiency of vitamin C than was induced in these experiments.
   Large doses of vitamin C can decrease monooxygenase activities in animals (131).
Such effects have been little studied in humans. Vitamin C administered in large doses
increased antipyrine clearance in one study (132) but not in another (133). A small
influence on warfarin disposition was not considered clinically significant (134). Large
doses of this vitamin may have effects on nonoxidative pathways of drug metabolism. For
example, the vitamin may reduce sulfate conjugation of drugs such as salicylamide and
acetaminophen by competing for available sulfate (135,136) (see Chapter 1).
   Administration of vitamin B6 can enhance the peripheral conversion of levodopa to
dopamine by dopa-decarboxylase, a pyridoxine-requiring enzyme, such that less is avail-
able to cross the BBB for conversion there to dopamine. Dopamine itself does not cross
the BBB. Carbidopa, an inhibitor of peripheral dopamine decarboxylase, which enhances
the efficacy and reduces side effects of levodopa, also prevents the reduction in efficacy
of levodopa by exogenous vitamin B6 (137).

   It is apparent that the variety of macronutrients and micronutrients found in foods can
have major effects on the metabolism and clinical effects of some drugs. There is incom-
plete understanding of many of these interactions, because experimental and clinical
observations are incomplete. It is likely also that there are many specific effects of dietary
components on drug metabolism and actions that remain to be discovered. Given the
complex mixture of chemicals found in foods and the large number of new drugs that
come to market yearly, interactions between dietary components and drugs will require
continued attention from investigators and health professionals in the future.
   Studies in healthy subjects indicated that diet may explain part of the intraindividual
variations in drug metabolism rates that occur over time (138). Further studies in relevant
patient populations on the effects on drug metabolism of naturally occurring dietary
variations are needed. As knowledge of these interactions increases, there will be an
increasing need for physicians, pharmacists, and drug manufacturers to provide informa-
168                                                          Part III / Influence of Food or Nutrients

tion on DNIs to patients. It must be kept in mind that public understanding of diet and
nutrition is less than desirable, and compliance with dietary recommendations is often not
satisfactory. Compliance is particularly difficult for individuals who are physically or
mentally impaired, or do not normally prepare their own food. Therefore, monitoring
strategies may be considered for some drugs that are particularly affected by changes
in diet.

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Chapter 9 / Grapefruit Juice–Drug Interactions                                           175

      9          Grapefruit Juice–Drug Interaction

                 David G. Bailey

   Medications and food are often taken together. Linking drug administration to a regu-
lar event like a meal can improve the patient’s adherence to the treatment regimen,
especially in the elderly (1). However, concomitant drug and food intake create the
opportunity for an interaction that may change (increase or decrease) drug benefit or
   The response to a drug is largely dependent on its concentration at the cellular site of
action (drug receptor). Increased drug concentration generally causes enhanced magni-
tude and duration of effect, whereas decreased drug concentration produces the opposite
result. The concentration at the drug receptor of an orally administered medication is
determined by the net result of oral bioavailability (rate and fraction of the oral dose of
drug absorbed into the systemic blood circulation), distribution from the circulation to the
drug receptor, and removal from the drug receptor.
   For most medications, absorption from the gastrointestinal (GI) tract occurs in the
proximal portion of the small intestines (duodenum). This is mainly owing to much
greater surface area and blood flow compared to the stomach. Before gaining access into
the systemic circulation, drugs must pass through the gut wall, enter the portal blood
circulation, and pass through the liver (Fig. 1). Mechanisms in both the gut wall and the
liver are capable of reducing drug bioavailability. This can occur by enzymatic conver-
sion of drug to derivatives (metabolites) at these sites, a process known as presystemic
or first-pass drug metabolism. Oral drug bioavailability is commonly determined by
measuring the systemic plasma drug concentration–time profile. A change in its rate (as
indicated by peak drug concentration [Cmax] and time to Cmax [tmax]), or extent (as deter-
mined by the area under the drug concentration–time curve [AUC]), can have important
implications for pharmacotherapy.
   More than 10 years ago, our group observed that grapefruit juice markedly increased
the rate and extent of oral bioavailability of the dihydropyridine calcium channel antago-
nist, felodipine. It was originally suggested from a secondary finding in an ethanol–drug
interaction study (2). In this investigation, grapefruit juice had been chosen to mask the
taste of the ethanol. Results showed that plasma drug concentrations were not different
                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
176                                                     Part III / Influence of Food or Nutrients

Fig. 1. Sequential presystemic felodipine metabolism by CYP3A4 in apical enterocytes of the
small bowel (A) and then the hepatocytes of the liver (B). The percent of unmetabolized felodipine
is presented before and after passage through the gut wall and the liver.

between felodipine plus ethanol (in grapefruit juice) or felodipine alone (with grapefruit
juice). However, both groups had concentrations that were several-fold higher than those
observed in other pharmacokinetic investigations in which the same dose of felodipine
was given with water. A systematic examination for obvious possible causes, such as
incorrect dose or drug assay problems, did not resolve this discrepancy. This eventually
resulted in a pilot project in a single volunteer to judge the possible role of the juice.
Plasma felodipine concentrations were more than fivefold higher with grapefruit juice
compared to those with water (3). Subsequently, the interaction was established in a
formal clinical study involving patients with untreated borderline hypertension (4). This
finding represented a new type of food–drug interaction and critically illustrated the
importance of unexpected observations in research.
Chapter 9 / Grapefruit Juice–Drug Interactions                                             177

    Felodipine has been the most extensively studied probe for grapefruit juice–drug
interactions. Normally, felodipine is completely absorbed from the GI tract following
oral administration (5). Thus, grapefruit juice did not act by improving drug dissolution
or other pharmaceutical property of the drug formulation. However, felodipine has low
inherent oral bioavailability averaging 15% (ranging from 4 to 36% among individuals)
from high presystemic metabolism (5,6). An enzyme belonging to the family of cyto-
chrome P450 (CYP) mixed-function oxidases is responsible. CYPs account for the
majority of oxidative biotransformations of drugs. This usually produces a metabolite(s)
that is (are) pharmacologically inactive or less active and more readily eliminated from
the body in urine. More than 50 different human CYPs have been identified. The nomen-
clature of CYPs is determined by similarity of amino acid composition. For example, the
enzyme CYP3A4 belongs to family 3 (40% identical amino acid sequencing) and sub-
family 3A (55% identical amino acids).
    CYP3A4 metabolizes felodipine (7–9) and many other medications. It is involved in
the metabolism of approx 60% of drugs that are oxidized (10). The location of CYP3A4
in the small intestine and liver makes it well suited to play a significant role in presystemic
drug metabolism (3,11). Intestinal CYP3A4 is found in apical enterocytes and varies
11-fold in protein content among individuals (12). Hepatic CYP3A4 content is much
higher and varies 20-fold among individuals. Intestinal and hepatic CYP3A4 content
appear to be regulated independently of each other (13).
    The first report showed that felodipine Cmax and AUC with grapefruit juice were
threefold those compared with orange juice or water (4). However, felodipine elimination
half-life (t1/2), i.e., rate of drug removal from the systemic circulation, was not different
among treatments. Also, intravenous pharmacokinetics of felodipine with grapefruit
juice were not changed (14). Thus, grapefruit juice primarily inhibited presystemic,
rather than systemic, metabolism of felodipine.
    Small intestinal enterocyte CYP3A4 protein content with grapefruit juice was reduced
by a mean 62% (15). Subjects with the highest enterocyte content of CYP3A4 before
grapefruit juice had the largest reduction of this enzyme and greatest increase in felodipine
Cmax with the juice. In contrast, liver CYP3A4 activity, as measured by the erythromycin
breath test, was not altered. Intestinal content of other drug metabolizing enzymes
(CYP2D6, CYP1A1) was not affected. Thus, grapefruit juice appeared to inhibit intes-
tinal CYP3A4 activity selectively.
    Decreased expression of intestinal CYP3A4 implied that the interaction was not the
result of just competition between felodipine and substrate(s) in grapefruit juice for
metabolism. Because the content of enterocyte CYP3A4 mRNA was not changed, the
interaction likely did not result from decreased production of CYP3A4 protein (15).
Rather, it indicated that the inhibitory effect was caused by enhanced degradation of this
enzyme. This effect could have been caused by a substance(s) in grapefruit juice that was
initially metabolized by CYP3A4 to a reactive intermediate(s) and then bonded covalently
to the enzyme, a process termed “suicide” or “mechanism-based” inhibition (3). The struc-
turally modified and inactivated CYP3A4 might then be expected to undergo rapid pro-
teolysis within the cell. Consequently, the return of CYP3A4 activity would require de
novo enzyme synthesis. Because reduced intestinal CYP3A4 protein by grapefruit juice
178                                                   Part III / Influence of Food or Nutrients

did not cause increased CYP3A4 mRNA, it indicated that there was not an effective
feedback mechanism within the enterocyte to up-regulate CYP3A4 synthesis. Thus, it
might be predicted that return of CYP3A4 activity would require enterocyte replacement.
This could cause prolonged inhibition of CYP3A4-mediated drug metabolism by grape-
fruit juice.
   The duration of inhibitory activity of grapefruit juice has been evaluated. In the initial
study, consumption of a single glass (200 mL) of grapefruit juice at various time intervals
before felodipine administration showed that the pharmacokinetic interaction was maxi-
mal between simultaneous and 4 hour previous juice consumption (16). Then, the extent
of the interaction declined slowly with increasing time interval. The half-life of disap-
pearance of inhibitory effect of grapefruit juice on CYP3A4-mediated drug metabolism
was estimated at 12 h. Increased felodipine Cmax was still evident when this volume of
grapefruit juice was consumed 24 h beforehand. Subsequently, two other studies using
two other drug probes, nisoldipine or simvastatin, confirmed the long duration of effect
of grapefruit juice (17,18). In the case of nisoldipine, increased drug AUC was observed
up to 72 h after a 7-d pretreatment period of grapefruit juice (200 mL) three times daily (17).
   Because grapefruit juice produced a long duration of inhibition of intestinal CYP3A4
activity, repeated administration of juice might be expected to cause a cumulative
increase in magnitude of pharmacokinetic interaction. Under single dose conditions,
mean felodipine Cmax and AUC with a glass of grapefruit juice (250 mL) were 3.5-fold
and 2.7-fold, respectively, of those compared to with water (15). During repeated juice
consumption, grapefruit juice (250 mL three times daily for 5 d) further increased
felodipine Cmax and AUC to 5.4-fold and 3.5-fold, respectively, of those relative to single
dose administration of felodipine with water. Thus, repeated administration of grapefruit
juice under certain conditions can cause a cumulative increase in the magnitude of the
pharmacokinetic drug interaction.

3.1. Medications Studied for an Interaction With Grapefruit Juice
   Many drugs from a broad range of therapeutic categories have been examined for a
possible interaction with grapefruit juice Those drugs that have increased oral
bioavailability with grapefruit juice are listed in Table 1 (4,9,19–78). Medications with-
out enhanced bioavailability are shown in Table 2 (79–100). Comparisons between these
tables supported the concept that medications interacting with grapefruit juice have low
to intermediate inherent oral bioavailability (<5 to 60%) and undergo presystemic
metabolism mediated primarily by CYP3A4. In general, drugs with lower bioavail-
ability have greater magnitude of interaction.

3.2. Adverse Effects With Grapefruit Juice
   The antiarrhythmic agents, amiodarone and quinidine, and the antimalarial drug,
halofantrine, can produce QTc interval prolongation and associated risk of developing
the life-threatening cardiac ventricular arrhythmia, torsade de pointes. Other medications
that produce this serious drug effect include the nonsedating antihistamines, astemizole
and terfenadine, and the GI prokinetic agent, cisapride. These latter medications have
Chapter 9 / Grapefruit Juice–Drug Interactions                                         179

          Table 1
          Drugs With Increased Oral Bioavailability With Grapefruit Juice
          Anti-Infective Agents                  Central Nervous System Agents
            Albendazole (19)                       Buspirone (52)
            Artemether (20)                        Carbamazepine (53)
            Erythromycin (21)                      Diazepam (54)
            Halofantrine (22)                      Midazolam (55,56)
            Praziquantil (23)                      Scopolamine (57)
            Saquinavir (24)                        Sertraline (58)
                                                   Triazolam (59,60)

          Anti-Inflammatory Agents               Estrogens
            Methyprednisolone (25)                  Ethinylestradiol (61)

          Antilipemic Agents                     Gastrointestinal Agents
            Atorvastatin (26)                      Cisapride (62–64)
            Lovastatin (27–29)
            Simvastatin (18,30)                  Histamine H1 Antagonists
                                                   Astemizole (65)
          Cardiovascular Agents                    Terfenadine (66–69)
            Amiodarone (31)
            Carvedilol (32)                      Immunosuppressive Agents
            Felodipine (4,9,14–16,33–39)           Cyclosporine (70–77)
            Nifedipine (40–42)                     Tacrolimus (78)
            Nimodipine (43)
            Nicardipine (44)
            Nisoldipine (17,45)
            Nitrendipine (46,47)
            Sildenafil (48)
            Verapamil (49–51)

been removed from the market because of this concern. The risk of developing this
arrhythmia appears to be increased in conditions where plasma concentrations of these
drugs are elevated.
   Mean oral bioavailability of amiodarone is normally variable among individuals (range:
20–80%) as a result of extensive first-pass metabolism (101). N-desethylamiodarone
(N-DEA) is the major metabolite formed by CYP3A4 (102). This metabolite appears to
have significant anti-arrhythmic properties. Mean amiodarone Cmax and AUC with grape-
fruit juice (300 mL at 0 h, 3 h, and 9 h relative to drug administration) were 1.8-fold and
1.5-fold those compared to amiodarone alone (31). This resulted in plasma amiodarone
concentrations that exceeded recommended therapeutic levels. Plasma N-DEA concen-
trations were decreased to undetectable levels and prolongation of QTc interval was less
with concomitant grapefruit juice. Inhibition of N-DEA production might decrease the
beneficial action of amiodarone or conversely it might reduce the unwanted proarrhythmic
effects linked to QTc prolongation. Because the clinical outcome is not clear, consump-
tion of grapefruit juice should be avoided in patients receiving amiodarone.
180                                                           Part III / Influence of Food or Nutrients

       Table 2
       Drugs Without Increased Oral Bioavailability With Grapefruit Juice
       Antiasthmatic Agents                                Antilipemic Agents
         Theophylline (79)                                   Pravastatin (26)

       Anticoagulants                                      Cardiovascular Agents
         Acenocoumarin (80)                                  Amlodipine (88,89)
         Warfarin (81)                                       Diltiazem (90,91)
                                                             Propafenone (92)a
                                                             Quinidine (93,94)a

       Anti-Infective Agents                               Central Nervous System Agents
         Amprenavir (82)                                     Alprazolam (95)
         Clarithromycin (83)                                 Clomipramine (96)
         Indinavir (84)                                      Clozapine (97)
         Itraconazole (85,86)                                Haloperidol (98)
         Quinine (86)                                        Phenytoin (99)

       Anti-Inflammatory Agents                            Estrogens
         Prednisone (74)                                      17 -Estradiol (100)
          aSee   text for discussion of concern for potential interaction.

   Quinidine has relatively high absolute oral bioavailability (about 70%) but it is has a
narrow therapeutic range of effective and safe plasma drug concentrations. In one single
dose study, grapefruit juice (240 mL) did not change mean quinidine Cmax or AUC;
however, it decreased 3-hydroxyquinidine AUC compared to water (93). In another
study, chronic consumption of grapefruit juice (250 mL twice daily) reduced the oral
clearance of quinidine and 3-hydroxy and N-oxide metabolites to 0.85, 0.81, and 0.73 of
those with water (94). Thus, grapefruit juice appears to have a small effect on mean
pharmacokinetics of quinidine. However, modestly elevated plasma quinidine concen-
trations have the potential to cause serious side effects. Thus, it seems reasonable to avoid
grapefruit juice consumption during therapy with quinidine until proven safe.
   Halofantrine has an oral bioavailability of 10% and is metabolized to the less car-
diotoxic metabolite, N-debutylhalofantrine, by CYP3A4 (105–107). When it was admin-
istered as a single dose after grapefruit juice (250 mL once daily for 3 d and once at 12
h before drug), halofantrine Cmax and AUC were 3.2-fold and 2.8-fold, respectively,
those with water (22). N-debutylhalofantrine AUC was decreased to 0.4-fold that observed
after water. Maximum QTc interval prolongation with halofantrine was increased to a
mean 31 ms with grapefruit juice compared to 17 ms with water. It was concluded that
consumption of grapefruit juice should be contraindicated during administration of
Chapter 9 / Grapefruit Juice–Drug Interactions                                           181

     -hydroxy- methylglutaryl-CoA (HMG-CoA) reductase inhibitors belong to an impor-
tant class of cholesterol-lowering medications. However, they can cause significant toxic-
ity. Unwanted effects range from diffuse myalgia and elevated creatine phosphokinase
to severe skeletal muscle degeneration (rhabdomyolysis) and associated acute renal fail-
ure. These effects can occur when plasma concentration of HMG-CoA reductase inhibi-
tor is markedly elevated.
   Atorvastatin, lovastatin, and simvastatin have low oral bioavailability as a result of
presystemic metabolism by CYP3A4. Atorvastatin is active and has a mean absolute oral
bioavailability of 12% (108). Simvastatin and lovastatin are prodrugs that are converted
by esterases to the corresponding active acid derivative. However, an alternative primary
metabolic pathway mediated by CYP3A4 is normally responsible for the inactivation of
the majority of lovastatin and simvastatin. This results in an absolute oral bioavailability
that is less than 5% (27,109). Although grapefruit juice augmented the plasma concen-
trations of atorvastatin, lovastatin, and simvastatin and active metabolites, the magnitude
of pharmacokinetic interaction was different. Atorvastatin AUC with grapefruit juice
was a mean 2.5-fold of that compared with water (26). In contrast, lovastatin and
simvastatin AUCs with grapefruit juice were at least 15-fold those observed with water
(27,30). Active metabolites were also increased. Thus, HMG-CoA reductase inhibitors
with lower inherent oral bioavailability from presystemic metabolism by CYP3A4 may
have greater risk of serious adverse effects with grapefruit juice. Regardless, it is recom-
mended that consumption of grapefruit juice should be avoided during therapy with
atorvastatin, lovastatin, or simvastatin.
   Pravastatin is metabolized by CYP3A4 to only a minor extent and shown not to interact
with grapefruit juice (26). Fluvastatin has essentially complete oral bioavailability and
is predominantly metabolized by CYP2C9. Thus, it would be predicted not to interact
with grapefruit juice. Pravastatin and fluvastatin might be considered as alternative agents
when there is concern for a potential interaction with grapefruit juice.
   Dihydropyridine calcium channel antagonists are selective arteriolar vasodilators that
are often employed in the management of hypertension or other cardiovascular disorders.
Adverse clinical consequences of excessive vasodilatation from elevated plasma concen-
tration of dihydropyridines include headache, ankle edema, and facial flushing. Although
these effects are generally not considered to be serious, they could be sufficiently unpleas-
ant to decrease patient compliance to the treatment regimen and to negate drug benefit. At
the other extreme, adverse drug events from excessive vasodilatation may result in symp-
tomatic hypotension or myocardial infarction.
   Several dihydropyridines have low inherent oral bioavailability and are inactivated, at
least in part, by CYP3A4-mediated metabolism. In middle-aged subjects with untreated
borderline hypertension, mean felodipine AUC with grapefruit juice was 2.8-fold that
compared with water (4). This was associated with enhanced diastolic blood pressure
reduction, heart increase and frequency of vasodilatation-related side events. In healthy
elderly individuals (70–83 yr of age), mean oral felodipine AUC with grapefruit juice was
2.9-fold that compared with water, supporting the importance of intestinal CYP3A4-
mediated drug metabolism in this age group (37). In contrast with the effect in middle-
182                                                 Part III / Influence of Food or Nutrients

age individuals, there was enhanced reduction of both systolic and diastolic blood pres-
sure in the elderly. Although some tachycardia was apparent in both age groups, lower
systolic blood pressure in only the elderly may have resulted from attenuated barorecep-
tor reflex responsiveness that is known to occur with aging (110). This likely also explains
the greater blood pressure-lowering effects of felodipine in the elderly (111). Because the
elderly appear more susceptible to hypotension-related adverse events, the interaction
between felodipine and grapefruit juice seems particularly relevant.
   Other dihydropyridines that interact with grapefruit juice include nifedipine (40–42),
nicardipine (44), nimodipine (43), nisoldipine (17,45), and nitrendipine (46,47). Average
dihydropyridine Cmax and AUC with grapefruit juice ranged from 1.5-fold to 4.0-fold
those with water under single dose conditions. In contrast, amlodipine has a negligible
pharmacokinetic interaction with grapefruit juice (88,89). Because amlodipine has inher-
ently high (80%) oral bioavailability, this appears to be the major reason.
   Sildenafil is used to treat erectile dysfunction by causing vasodilatation of smooth
muscle of the corpus cavernosa. At therapeutic drug concentration, sildenafil inhibits a
form of phosphodiesterase (PDE5) to increase intracellular cyclic guanosine monophos-
phate (cGMP) concentration selectively in this tissue. At higher drug concentration, the
selectivity of sildenafil for PDE5 is lost and other forms of PDE are inhibited, resulting
in a generalized increase in intracellular cGMP and systemic vasodilatation. Nitrates can
also increase intracellular cGMP concentration but this is by a mechanism involving
stimulating cGMP production. The combined effects of sildenafil and nitrates can be
sufficient to cause symptomatic hypotension, myocardial infarction or sudden death.
Sildenafil has intermediate oral bioavailability (mean: 41%, range: 25%–63%) and is
cleared extensively through metabolism mediated by CYP3A4 (112,113). The primary
metabolite (N-desmethylsildenafil) is approx 50% as potent as the parent drug. Sildenafil
and desmethylsildenafil AUCs with grapefruit juice (250 mL) given before (1 h) and
together with drug were a mean 1.2-fold those compared to water in a single dose study
(48). Mean decrease in systolic and diastolic blood pressure and increase in heart rate
were not different between treatments. However, sildenafil AUCs with grapefruit juice
ranged from 0.8-fold to 2.6-fold those compared to water among individuals. The authors
concluded that the small increase in the mean oral bioavailability of sildenafil and active
metabolite by grapefruit juice would probably not produce more enhanced therapeutic or
adverse effects. However, variability in the extent of the pharmacokinetic interaction
among individuals, in the amount of CYP3A4 inhibitors among brands and batches of
grapefruit juice and in the volume of juice consumed make the effect less predictable. It
was recommended that the combination of sildenafil and grapefruit juice should be
   Verapamil depresses atrioventricular conduction and myocardial contractility and
dilates arteriolar smooth muscle. Verapamil is a racemic mixture of S- and R-enanti-
omers. The S-enantiomer is more pharmacologically active. Verapamil undergoes
stereoselective first-pass metabolism involving CYP3A4 that results in variable
bioavailability of 13–34% for the S-enantiomer and 33–65% for the R-enantiomer among
individuals. In one study, administration of a single glass of grapefruit juice (200 mL) to
10 hypertensive patients receiving chronic short-acting verapamil resulted in increased
Chapter 9 / Grapefruit Juice–Drug Interactions                                            183

AUC ratio of racemic parent drug to major active dealkylated metabolite, norverapamil,
indicative of inhibition of verapamil metabolism (49). However, the absolute pharmaco-
kinetic values for verapamil and norverapamil were not changed. In a second study,
grapefruit juice (200 mL twice daily for 5 d) increased steady-state plasma concentrations
of both S- and R-enantiomers of verapamil compared to orange juice control (50). Mean
AUC and Cmax of S-verapamil with grapefruit juice were 1.4-fold and 1.6-fold those with
orange juice, respectively. The effect was similar for R-verapamil. Considerable
intersubject variability in the magnitude of the pharmacokinetic interaction was appar-
ent. No change in the mean pharmacodynamics of verapamil (blood pressure, heart rate,
PR interval <350 ms) was observed. In the third study, grapefruit juice (1 L per day for
3 d) augmented the steady-state plasma concentration of S,R-verapamil administered in
the prolonged release drug formulation (51). Mean verapamil AUC and Cmax with grape-
fruit juice were 2.5-fold and 2.6-fold of those compared with water. The increases were
slightly greater for verapamil than for norverapamil. Prolongation of PR interval
above 350 ms occurred in two of the 24 individuals in the group receiving grapefruit
juice. The results of these studies show that a pharmacokinetic interaction can occur
with verapamil under most conditions of concomitant grapefruit juice administra-
tion. However, a pharmacodynamic interaction was evident only during chronic
verapamil and repeated high-volume grapefruit juice consumption. Nevertheless, the
high variability of the pharmacokinetic interaction among individuals suggests that a
clinically relevant interaction may occur with verapamil under single-dose and more
usual volumes of grapefruit juice administration.
   Losartan antagonizes the vasoconstrictor and aldosterone stimulating effects of angio-
tensin II. It undergoes substantial first-pass metabolism resulting in a mean absolute oral
bioavailability of 33%. Losartan is partially converted by CYP3A4 and CYP2C9 to the
active carboxylic acid metabolite, E-3174, that is responsible for the majority of angio-
tensin II receptor antagonism. E-3174 AUC with grapefruit juice was reduced compared to
that with water, suggesting that the therapeutic effectiveness of losartan may be decreased
by grapefruit juice (114).
   Carvedilol combines nonselective -receptor and -1 receptor blockade in a single
racemic drug. -Receptor blockade is attributed to the S-enantiomer, whereas -1 recep-
tor blockade is present in equal potency in both enantiomers. Because heart failure can
worsen when and receptor blockade are excessive, care must be taken in situations
where plasma S,R-carvedilol concentrations are increased. Although racemic carvedilol
is well absorbed from the GI tract, it has only a 25–35% absolute oral bioavailability
because of presystemic metabolism. This process is stereoselective and results in plasma
concentrations of S-carvedilol that are twofold to threefold lower than those of R-carvedilol.
Glucuronidation and oxidation by CYP2D6 and CYP2C9 appear to be the major pathways
of drug elimination. Consequently, it might be predicted that grapefruit juice would not
significantly interact with carvedilol. Results of a clinical investigation showed that mean
AUC of S,R-carvedilol with grapefruit juice (300 mL) was 1.2-fold that of water under
single dose conditions (32). Unfortunately, the magnitude of the interaction among indi-
viduals and the effect on each enantiomer was not reported. Because dosage and effect of
carvedilol must be carefully individualized and closely monitored by a physician expe-
184                                                 Part III / Influence of Food or Nutrients

rienced in the treatment of heart failure, this makes a recommendation about grapefruit
juice use in this setting unclear. For no other reason than to eliminate factors that might
prevent establishment of a stable dose–response relationship, it seems reasonable to
indicate that patients with heart failure receiving carvedilol should avoid grapefruit juice
3.3. Potential Beneficial Effects With Grapefruit Juice
   Cyclosporine is an immunosuppressive agent useful in preventing organ rejection
following transplantation. It is crucial that plasma cyclosporine concentrations are main-
tained within a narrow range so as to have adequate drug concentration to prevent trans-
plant rejection but not to have sufficiently high concentration to cause renal toxicity.
Cyclosporine is very expensive and must be taken on a daily basis for many years.
Cyclosporine has a 30–40% oral bioavailability. Theoretically, increasing cyclosporine
bioavailability could result in reduced drug dose and associated cost. Cyclosporine is
metabolized by CYP3A4. Thus, grapefruit juice might be useful in this situation. Several
investigations have shown that grapefruit juice can increase cyclosporine bioavailability
(70–77). However, the effect was variable among studies. Also, there is the absolute need
for consistency of effect among batches and suppliers of the juice. Practically, it may not
be possible to maintain a uniform effect on cyclosporine bioavailability. Thus, grapefruit
juice is currently not recommended as a means to reduce drug cost in this circumstance.
   Artemether is an antimalarial drug with fast onset of action, few side effects, and good
activity against multidrug-resistant parasites. However, it has a high relapse rate during
monotherapy. Because there is marked reduction in plasma drug concentrations on repeated
administration, induction of its own metabolism (autoinduction) is considered the cause of
loss of efficacy. Artemether undergoes high presystemic metabolism by CYP3A4. Dur-
ing single dose administration, grapefruit juice increased the oral bioavailability of
artemether compared to water (115). After 5 d of concomitant grapefruit juice adminis-
tration, higher plasma artemether concentrations were observed compared to those with
5 d of water. However, both grapefruit juice and water produced decreased oral
bioavailability of artemether over this time period. Thus, grapefruit juice improved the
oral bioavailability of artemether under conditions of single and repeated administration.
However, grapefruit juice did not totally abolish the autoinduction of artemether. Nev-
ertheless, it prolonged effective plasma drug concentrations. Oral treatment with
artemether may be more effective when the medication is taken with grapefruit juice.
   Protease inhibitors are antiretroviral drugs used in the treatment of HIV-1 infection.
Saquinavir has very low oral bioavailability (1–2%) and is a substrate for CYP3A4.
Because it does not have toxicity at high plasma drug concentration, any increase in
saquinavir bioavailability has the potential to produce only enhanced drug benefit.
Saquinavir AUC with grapefruit juice was twofold that with water (24). Although
saquinavir with grapefruit might produce some therapeutic benefit compared to saquinavir
alone, the extent of the interaction was minor compared to the 58-fold increase seen with
ritonavir (116).
Chapter 9 / Grapefruit Juice–Drug Interactions                                         185

                     Table 3
                     Drugs That May Interact With Grapefruit Juice
                     Inhibition of Intestinal CYP3A4
                     Inhibition of Intestinal P-glycoprotein
                     Inhibition of Intestinal Organic Anion
                     Transporting Polypeptides

4.1. Incomplete List of Interacting Drugs
   A substantial number of drugs have been assessed for an interaction with grapefruit
juice. However, many more medications have not been studied. Nevertheless, it is pos-
sible to predict the likelihood of an interaction for other drugs. Because grapefruit juice
enhances oral drug bioavailability, the suspected medication should have an inherent
absolute bioavailability that is normally low or intermediate (<60–70%). Additionally,
there should be accompanying data to indicate that the drug is extensively metabolized
by CYP3A4. Drugs with such a potential to interact with grapefruit juice are listed in
Table 3.
   The antiplatelet agent, clopidogrel, is an irreversible inhibitor of adenosine 5'diphos-
phate-induced platelet aggregation and is used for secondary prevention of vascular
events in patients with history of symptomatic atherosclerotic disease. It is rapidly con-
verted to at least one active metabolite, which results in plasma clopidogrel concentration
that is normally not detectable following oral administration. Although the active
metabolite(s) has not been identified, recent findings have shown that concomitant
administration of a CYP3A4 inhibitor, erythromycin or troleandomycin, attenuated
platelet aggregation inhibition; whereas, pretreatment with a CYP3A4 inducer, rifampin,
enhanced platelet aggregation inhibition (117). Consequently, the active metabolite(s) of
clopidogrel is (are) likely formed by CYP3A4. Because clopidogrel has negligible oral
bioavailability, extensive presystemic metabolism by intestinal CYP3A4 might be
expected. Consequently, grapefruit juice could reduce formation of the active
metabolite(s) and attenuate the therapeutic benefit of clopidogrel.
   Ergotamine is an alkaloid used to treat migraine headache. Serious toxicity can occur
during therapy. Ergotism is a syndrome referred to as “St Anthony’s Fire” and is char-
acterized by vascular ischemia and neurological compromise as a result of excessive
186                                                  Part III / Influence of Food or Nutrients

ergotamine concentration. Cases of gangrene and stroke have been reported that have
resulted in amputation or death. Ergotamine appears to have low oral bioavailability and
is a substrate of CYP3A4 (118). Toxicity has occurred in patients concomitantly receiv-
ing standard doses of ergotamine with the CYP3A4 inhibitors, clarithromycin, ritonavir,
or triacetyloleandomycin (119). Thus, an interaction between ergotamine and grapefruit
juice appears probable and this combination should be avoided. Alternatively, better
options for the treatment of migraine headache include the class of drugs known as
triptans. There does not appear to be an interaction between most drugs of this class and
grapefruit juice.
    Propafenone undergoes presystemic metabolism resulting in an absolute oral
bioavailability that ranges from 3 to 40%. Normally, the major route of elimination is
metabolism by CYP2D6 and the minor route involves metabolism by CYP3A4. How-
ever, the activity of CYP2D6 varies markedly among individuals. Genetic mutations can
result in CYP2D6 activity that is markedly reduced or absent, a phenomenon known as
“genetic polymorphism.” The frequency–activity distribution curve of CYP2D6 is
divided into two basic populations classified as extensive (EM) or poor (PM)
metabolizers. The incidence of CYP2D6 PM is 5–10% in Caucasians and about 1% in
Asians. Preliminary data indicate that CYP3A4 inhibitors, erythromycin, ketoconazole,
or grapefruit juice, can increase plasma propafenone concentrations in individuals who
are CYP2D6 PM (92). Symptoms of propafenone overdose include bradycardia, hypoten-
sion, conduction disturbances, ventricular tachycardia and/or fibrillation, somnolence, or
convulsions. This may explain the adverse interaction in a patient taking propafenone for
4 yr who experienced convulsions 2 d after starting treatment with the CYP3A4 inhibitor,
ketoconazole (120). Thus, grapefruit juice may potentially cause propafenone toxicity in
individuals who are CYP2D6 PM.
    Repaglinide is an oral antidiabetic agent that reduces blood glucose by stimulating
insulin release from pancreatic -cells. It has a mean absolute oral bioavailability of about
50% and is inactivated by metabolism involving CYP3A4. Four days pretreatment with
the CYP3A4 inhibitor, clarithromycin, produced repaglinide Cmax and AUC that were
1.7-fold and 1.4-fold those without clarithromycin (121). Although insulin concentration
was elevated, blood glucose concentration was not altered. Concomitant use of grapefruit
juice might enhance plasma repaglinide concentrations and increase the risk of hypogly-
cemia. This may be particularly important for the elderly who are particularly susceptible
to the hypoglycemic action of glucose-lowering drugs and who are the major consumers
of grapefruit juice.
    Sibutramine reduces body weight by enhancing satiety and inducing thermogenesis
through inhibition of neuronal reuptake of serotonin and noradrenaline. Sibutramine
appears to undergo extensive CYP3A4-mediated presystemic metabolism to active
metabolites. Concomitant administration of the CYP3A4 inhibitors, ketoconazole or
erythromycin, produced mean sibutramine Cmax that were twofold or threefold, respec-
tively, those compared to sibutramine alone (122). The Cmax of at least one active metabo-
lite was also increased. Systolic and diastolic blood pressures and heart rate were increased
compared to sibutramine alone. Because caution is recommended for administration of
sibutramine with CYP3A4 inhibitors, it may also be appropriate to include avoidance of
grapefruit juice. As patients might consider the “grapefruit diet” as an adjunct to weight
reduction, this precaution appears particularly relevant.
Chapter 9 / Grapefruit Juice–Drug Interactions                                              187

5.1. Inhibition of Drug Transport Mediated by P-Glycoprotein
    Transporters are increasingly recognized as important determinants of drug disposition
and resulting clinical response. The best-characterized drug transporter is P-glycoprotein
(P-gp). P-gp was first observed in tumor cells where it caused drug resistance to chemo-
therapeutic agents. Subsequently, P-gp was shown to play an important physiological
role. P-gp is an adenosine 5'-triphosphate-dependent efflux pump located on the luminal
surface of epithelial cells of the small intestine, the bile canalicular membrane of the liver,
and the proximal tubule of the kidney. It is also located on endothelial cells that comprise
the blood–brain and blood–testes barriers. P-gp affects the disposition of drugs by limiting
their absorption from the gut, by facilitating their removal through secretion into bile and
urine, and by reducing their entry into brain and testes (see Chapter 3).
    The effect of grapefruit juice on P-gp has not been as extensively documented com-
pared to its effect on CYP3A4. In one study, repeated administration of grapefruit juice
(250 mL three times daily for 5 d) did not appear to alter enterocyte P-gp content in
humans (15). However, a nonspecific antibody for detecting P-gp had been used. Thus,
it is currently not clear whether grapefruit juice can decrease enterocyte P-gp expression
as it does for CYP3A4 expression (15). Other results suggest that grapefruit juice can
modulate P-gp activity. This conclusion is based on the effect of grapefruit juice relative
to that of Seville (sour) orange juice. In one investigation, both juices decreased enterocyte
CYP3A4 content and augmented the oral bioavailability of felodipine, a drug metabo-
lized by CYP3A4 but not transported by P-gp (39). In another study, only grapefruit juice
increased the oral bioavailability of cyclosporine, a medication metabolized by CYP3A4
and transported by P-gp (123). Thus, grapefruit appeared to increase drug bioavailability
by an additional mechanism to inactivation of intestinal CYP3A4 that may involve inhi-
bition of P-gp. In contrast, grapefruit juice increased (9%, p = 0.01) the oral bioavailability
of the nonmetabolized P-gp substrate, digoxin, in humans (124). This prompted the
authors to conclude that grapefruit juice did not relevantly inhibit intestinal activity of P-
gp in humans. However, digoxin normally has an oral bioavailability of 70–80%. Thus,
inhibition of P-gp in the GI tract would not be expected to enhance the absorption of
digoxin. Furthermore, data from other sources support an effect on P-gp activity. For
example, grapefruit juice increased plasma concentrations of the nonmetabolized P-gp
substrate, talinolol, following oral administration to rats (125). Also, grapefruit juice inhib-
ited P-gp-mediated drug transport in certain in vitro studies (126,127). On the other hand,
grapefruit juice was reported to activate this transporter in one in vitro study (128).
However, the authors later attributed this finding to equipment artifact (39). Thus, infor-
mation from a number of different sources imply that grapefruit juice can inhibit intes-
tinal P-gp activity. However, the clinical relevance of this effect requires further
    The angiotensin II receptor blockers, eprosartan, telmisartan, and valsartan, have low
absolute oral bioavailability reported as 13, 43, and 23%, respectively. Although they are
excreted essentially unchanged, biliary clearance is important for the systemic elimina-
tion of these drugs. Because P-gp in the liver plays an important role in the canalicular
secretion of drugs into bile, P-gp in the GI tract may be responsible for the low oral
bioavailability of these angiotensin II receptor blockers. Consequently, grapefruit juice
might augment the oral bioavailability of candesartan, eprosartan, telmisartan, or valsartan.
188                                                  Part III / Influence of Food or Nutrients

5.2. Inhibition of Drug Transport by Organic Anion Transporting
   Drug absorption from the GI tract and distribution into tissues are generally considered
to be mediated primarily by passive diffusion. However, recent findings indicate that a
family of drug uptake transporters known as organic anion transporting polypeptides
(OATPs) might play an important role for certain medications. In the small intestine,
OATP transporters are located on the luminal membrane of enterocytes and enable drug
uptake from the GI tract into the portal circulation. In the liver, they are found on the
sinusoidal membrane and facilitate the movement of drug from portal circulation into
   Grapefruit, orange, and apple juices were recently shown to reduce markedly the oral
bioavailability of the nonmetabolized antihistamine, fexofenadine, a substrate for both
P-gp and OATPs (129). In vitro studies demonstrated that these juices and certain con-
stituents (furanocoumarins and bioflavonoids) were much less potent inhibitors of P-gp
compared to OATPs. These initial findings appear to represent a new mechanism for
food–drug interactions involving inhibition of drug uptake transporters by grapefruit or
other fruit juices. It may help explain the recent observations that the oral bioavailability
of etoposide and celiprolol were decreased by grapefruit juice (130,131).

   Drug-related issues such as pharmacokinetics, mechanism of elimination, and toxicity
play critical roles when assessing potential risk of an interaction with grapefruit juice. If
a medication has low oral bioavailability from high presystemic metabolism mediated by
CYP3A4 and can produce serious overdose toxicity, it appears mandatory to advise
against concomitant consumption of grapefruit juice. Although this may not cause altered
drug response in most instances, it is often difficult to predict. Consequently, avoiding
the combination will definitely prevent toxicity. Also, alternative medications that don’t
interact with grapefruit juice are often available.
   Patient-related issues affect the clinical importance of the interaction. The magnitude
of pharmacokinetic interaction is normally markedly variable. For example, felodipine
AUC with grapefruit juice can range from no change to eightfold that with water among
individuals (9,15,33). This difference appears dependent on intestinal CYP3A4 content
such that patients with the highest amount of CYP3A4 before consuming grapefruit juice
are the ones that show the greatest increase in drug concentration (15). Unfortunately,
there are no routine clinical tests available to estimate the extent of pharmacokinetic
interaction before exposure. Pre-existing medical conditions can also affect clinical
response. For example, dihydropyridines produce an antihypertensive effect depen-
dent on pretreatment blood pressure. The greatest reduction in blood pressure occurs in
patients with the highest pretreatment blood pressure (111,132). These patients are likely
at greater risk of developing cardiovascular ischemic symptoms with the combination of
a dihydropyridine and grapefruit juice. Age appears to affect susceptibility to drug inter-
actions. For example, elderly patients have demonstrated enhanced antihypertensive
effect to dihydropyridines compared to younger individuals (4,37). As mentioned previ-
ously, this may result from reduced autonomic responsiveness from age-related decreased
baroreceptor sensitivity (110). Because the elderly are the group most often prescribed
Chapter 9 / Grapefruit Juice–Drug Interactions                                                        189

medications and are major consumers of grapefruit juice, the potential for a relevant
unwanted grapefruit juice–drug interaction in this population appears substantial.
    Administration-related issues require consideration as well. First, grapefruit juice
appears to have the potential to interact only with drugs that are administered orally
(14,70). Second, commercial white grapefruit juice from frozen concentrate, diluted
from concentrate or fresh frozen has been shown to interact with felodipine (4,9,14–
16,33–37,39). Segments from unprocessed grapefruit can do the same (38). Thus, any
form of grapefruit should be considered to produce a drug interaction. Third, consump-
tion of a single glass of a normal amount of regular-strength grapefruit juice (200 mL)
can produce a clinically relevant increase in oral drug bioavailability (14,16,34). Because
administration of the same volume of double-strength juice did not substantially enhance
this effect, it appears that as little as 200 mL of regular-strength grapefruit juice can
produce near maximal acute pharmacokinetic interaction (34). Fourth, chronic consump-
tion of grapefruit juice several times daily should be considered to produce a cumulative
inhibitory effect on intestinal CYP3A4 and enhanced the magnitude of the drug interac-
tion (15). Fifth, high consumption of grapefruit juice may also inhibit hepatic CYP3A4
(60). Sixth, the amount of active ingredient(s) in grapefruit may vary among batches and
lots that may affect reproducibility of the interaction. Seventh, grapefruit juice has a very
long duration of action (16–18). A glass of grapefruit juice consumed one day has the
potential to augment the oral bioavailability of drug administered the next day. Thus, it
is recommended that grapefruit juice consumption should best be avoided entirely during
pharmacotherapy, rather than just for concomitant juice and drug administration, when
there is a concern for drug toxicity from excessive plasma drug concentration.

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Chapter 10/Nutrients and Drug Effects                                                     195

   10            Nutrients That May Optimize
                 Drug Effects

                 Imad F. Btaiche and Michael D. Kraft

   Drug–nutrient interactions (DNIs) are often the result of physical and chemical inter-
actions between drugs and nutrients. These interactions are influenced by several factors
that can be defined as either physical–chemical properties (e.g., pH, dissolution, disin-
tegration, binding) or physiological determinants (e.g., absorption and elimination pro-
cess, gastrointestinal [GI] transit time, GI secretions, splanchnic blood flow, liver enzyme
inhibition, or induction) (1,2). Clinically significant DNIs may result in therapeutic
failure, drug toxicity, or nutrient deficiency. Less commonly considered, DNIs may even
enhance drug effect. This chapter focuses on some clinically relevant DNIs that result in
a beneficial increase of drug effect or reduction of drug toxicity.

2.1. Albendazole
    Albendazole is a broad-spectrum anthelmintic agent effective against larval and adult
stages of trematodes and cestodes (3). Albendazole is available in oral tablets. Owing to
its low aqueous solubility, albendazole is poorly absorbed from the GI tract. However,
administration with a fatty meal enhances albendazole solubility and increases its
    Fatty meals increase the oral bioavailability of albendazole up to fivefold as compared
to fasting. Maximal plasma concentrations of albendazole sulfoxide (primary active
metabolite) were achieved in 2–5 h with albendazole 400 mg doses during treatment of
patients with hydatid disease (4). In a study that assessed the bioavailability of albendazole
in six hydatid disease patients, mean plasma albendazole concentrations were 4.5 times
higher when albendazole was administered with breakfast as compared to fasting (5). In
another study of adult patients with onchocerciasis, plasma albendazole sulfoxide concen-
trations increased fourfold when albendazole was administered with breakfast (43.1 g of
fat) instead of on an empty stomach (6). However, when given with 20 mL of olive oil
in 100 mL of milk to four adult volunteers, plasma albendazole sulfoxide concentra-
tions increased 3.5-fold in one subject, whereas only small changes occurred in the other
three subjects (7).

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
196                                                    Part III/Influence of Food or Nutrients

   Albendazole absorption is significantly increased when taken with food. Albendazole
should be administered with fatty meals to increase albendazole concentrations within
tissues and hydatid cysts (4). However, administration of albendazole on an empty stom-
ach is preferable when albendazole intraluminal effects are desired to treat susceptible
intestinal parasites (3,5).
2.2. Atovaquone
   Atovaquone is an antiprotozoal agent available in oral suspension form. Atovaquone
is used as second-line agent for treatment and prophylaxis of mild to moderate
Pneumocystis carinii pneumonia in patients who are intolerant to trimethorpim-
sulfamethoxazole. The lipohilic and low aqueous solubility of atovaquone makes it slowly
and irregularly absorbed on an empty stomach. However, atovaquone bioavailability is
enhanced when taken with a fatty meal. The previously marketed atovaquone tablet
resulted in irregular absorption and subtherapeutic plasma concentrations. As such,
manufacturing of atovaquone tablets (Mepron ) was discontinued since the suspension
became available. Atovaquone suspension had a twofold increase in bioavailability as
compared to the tablet (8), resulting in increased atovaquone area under the concentra-
tion-time curve (AUC) and increased peak plasma concentrations (Cmax) (9).
   In a prospective open-label crossover study of 10 healthy volunteers, a single 750
mg dose of atovaquone suspension resulted in significantly increased atovaquone
bioavailability when administered following breakfast (fat content 21 g) or following
an oral liquid nutrition supplement (Sustacal Plus : fat content 28 g). Atovaquone AUC
following breakfast (103.8 µg.h/mL) and Sustacal Plus (118.8 µg.h/mL) were signifi-
cantly greater as compared to fasting (43.4 µg.h/mL) (p < 0.0001). This corresponds to
a mean increase in atovaquone bioavailability by 502% and 505% following breakfast
and Sustacal Plus , respectively (10).
   Two studies investigated the effect of food on the pharmacokinetics of atovaquone
suspension in patients infected with the human immunodeficiency virus (HIV) (11,12).
In an open-label, dose-escalation study including 22 HIV-infected patients, administra-
tion of atovaquone with breakfast (23 g fat) increased average atovaquone steady-state
plasma concentrations by 1.3- to 1.7-fold as compared to fasting (11). Similarly, a single-
and multiple-dose pharmacokinetic study in HIV-infected patients showed food to
increase atovaquone bioavailability by 1.4-fold. However, increased incidence of rash
was observed when higher plasma atovaquone concentrations were achieved with the
1000 mg twice-daily dose taken with food (12).
   In summary, the rate and extent of atovaquone absorption are significantly increased
when taken with food, especially fatty meals. As such, atovaquone should be administered
with meals to increase its absorption and improve its therapeutic effects (8).
2.3. Cefuroxime
   Cefuroxime is a broad-spectrum -lactam antibiotic belonging to the second-genera-
tion cephalosporins. Cefuroxime has a broad activity against susceptible bacteria causing
infections of the upper and lower respiratory tract, skin and soft tissues, and the genitouri-
nary tract (13). Cefuroxime is available as the prodrug cefuroxime axetil in oral suspen-
sion and tablet dosage forms, and as cefuroxime for intravenous administration (14).
Cefuroxime axetil is rapidly absorbed from the GI tract and is hydrolyzed to active
cefuroxime once in the bloodstream (13–15). The oral tablet and suspension forms of
Chapter 10/Nutrients and Drug Effects                                                 197

cefuroxime axetil are not bioequivalent and cannot be used interchangeably (14). The
safety and efficacy of oral cefuroxime tablet and suspension were established in separate
clinical trials, and the dosage forms have different therapeutic indications (13,14).
Since cefuroxime axetil oral tablet form became available, it has been reformulated
several times due to absorption problems (15). Food (16–18) and milk (19) have been
shown to enhance cefuroxime axetil bioavailability, but the exact mechanism of this
effect remains unknown.
   In a randomized, crossover, open-label study that evaluated the effects of food and
fasting on cefuroxime bioavailability in healthy volunteers, mean cefuroxime absolute
bioavailability during fasting was 32–35%. There was a 34% increase in relative
bioavailability when cefuroxime axetil was taken with food (AUC: 50 µg·h/mL) as
compared to fasting (AUC: 36.4 µg·h/mL). Compared to fasting, food also resulted in
increases of the Cmax (13.9 µg/mL vs 9.9 µg/mL) and the time to peak concentration
(Tmax: 2.7 h vs 2.1 h, respectively). Cefuroxime elimination half-life was not signifi-
cantly changed (16). In another study, similar food effects on cefuroxime absorption
were observed. A single 500 mg dose of cefuroxime axetil taken with food resulted in
increased absolute cefuroxime bioavailability from 36 to 52%, corresponding to a rela-
tive increase in cefuroxime bioavailability by 45%. There was also a linear correlation
between cefuroxime single doses ranging from 125–1000 mg given with food and both
the AUC (r2 = 0.958) and Cmax (r2 = 0.943) (17).
   A study evaluated the effects of food and increased gastric pH (with administration of
ranitidine and sodium bicarbonate) on cefuroxime absorption in six healthy volunteers.
Cefuroxime administration with food resulted in increased cefuroxime bioavailability
despite the anticipated negative effects of increased gastric pH on cefuroxime absorption.
Cefuroxime bioavailability significantly increased with food as compared to fasting
(AUC: 39.8 2.9 µg·h/mL vs 23.4 2.9 µg·h/mL, p < 0.05). The Tmax was signifi-
cantly longer when cefuroxime was taken with food as compared to fasting (13.6
1.0 h vs 7.3 0.8 h, p < 0.05). The Cmax was slightly higher in the fed state, but this
was statistically significant (20).
   In a study that evaluated the effects of food on serum cefuroxime concentrations and
the minimum inhibitory concentration (MIC), serum cefuroxime concentrations were at
or above the MIC of common respiratory pathogens for the majority of the dosing interval
(18). This suggests that administration of cefuroxime axetil with food achieves adequate
serum levels for the effective treatment of susceptible organisms (13,18).
   There are pharmacokinetic differences between the cefuroxime tablet and suspension
forms (13–21). In one study, the AUC and Cmax for cefuroxime suspension averaged 91
and 71% of that for the tablet, respectively (13). In another study, cefuroxime adminis-
tration with meals resulted in significantly lower AUC for oral cefuroxime suspension as
compared to the tablet (10.22 µg·h/mL vs 14.02 µg·h/mL, respectively; p = 0.001). Food
also resulted in significantly lower Cmax with cefuroxime suspension as compared to the
tablet (2.48 µg/mL vs 4.04 µg/mL, respectively; p = 0.001). Despite these differences,
serum cefuroxime bactericidal activities were not affected and remained similar with
both dosage forms (21).
   In summary, cefuroxime axetil tablets should preferably be administered with food or
milk to enhance absorption. Oral cefuroxime suspension provides an alternative to the
tablet, especially in those who cannot swallow the tablet. Patients with elevated
intragastric pH should take cefuroxime tablets with food to enhance absorption.
198                                                    Part III/Influence of Food or Nutrients

2.4. Griseofulvin
   Griseofulvin is an oral antifungal agent used for treatment of tinea infections. Because
of its low aqueous solubility, griseofulvin absorption is slow, irregular, and incomplete,
especially when taken on an empty stomach (22). However, griseofulvin absorption in-
creases by twofold when griseofulvin is taken with fatty meals (23). Food appears to
increase griseofulvin absorption by increasing its disintegration and de-aggregation (24).
   In a study of 12 adult volunteers who received a single 500 mg tablet of griseofulvin,
a significant increase by 70 and 120% in griseofulvin bioavailability occurred following
intake of a low-fat (29.3% calories from fat) and high-fat (52.4% calories from fat) meal,
respectively, as compared to fasting (p < 0.01) (25). One study, however, concluded that
fatty meals increase the rate but not the extent of griseofulvin absorption, and that griseof-
ulvin follows a circadian rhythm of absorption regardless of dietary fat content (26).
   Griseofulvin absorption also varies with the dosage form used. A crossover study of
four healthy volunteers compared the absorption of two different dosage forms consist-
ing of microsize and ultramicrosize griseofulvin tablets taken with or without food. When
taken on an empty stomach, griseofulvin Cmax of the ultramicrosize formulation was
about 70% of the microsize formulation. When taken with food, griseofulvin Cmax was
136% of the microsize formulation and about twice the Cmax for the ultramicrosize
formulation. The rate and extent of griseofulvin bioavailability were similar for both
formulations when taken with food (24).
   In summary, optimal plasma griseofulvin concentrations are attained when griseoful-
vin is administered with a high-fat meal. As such, taking griseofulvin with meals maxi-
mizes its absorption and enhances therapeutic drug effect.
2.5. Isotretinoin
   Isotretinoin is a synthetic analog of vitamin A available in oral capsules. Isotretinoin
is primarily used for treatment of cystic acne. Isotretinoin is a highly lipophilic drug with
maximal isotretinoin absorption achieved when administered with a fatty meal (27).
   The effects of food and fasting on isotretinoin bioavailability were evaluated in a
randomized crossover study of 20 healthy male volunteers. An 80 mg oral dose of
isotretinoin was administered either during a complete fast, 1 h before a standard break-
fast, with a standard breakfast, or 1 h after a standard breakfast. Each treatment was
separated by a washout period. Study results showed that isotretinoin bioavailability
increased by about 1.5- to 2-fold when isotretinoin was administered 1 h before, with, or
1 h after breakfast, as compared to fasting. Mean Cmax increased 1.6- to 2.4-fold in the
presence of food but Tmax was slightly delayed by 0.8–1.6 h. The investigators related the
positive effects of food on isotretinoin absorption to increased bile flow that enhances
isotretinoin solubility (28).
   In summary, isotretinoin bioavailability is increased when the drug is taken with food.
Consistent intake of isotretinoin with meals is recommended in order to maximize
isotretinoin clinical effects.
2.6. Itraconazole
   Itraconazole is a triazole antifungal used for treatment of superficial and systemic
fungal infections. Itraconazole is available in oral solution and capsule, and as an inject-
able form for intravenous administration. Each itraconazole dosage form has specific
indications (29). Itraconazole is a highly lipophilic, extremely weak base that is almost
Chapter 10/Nutrients and Drug Effects                                                    199

insoluble in water and requires an acidic medium for optimal oral absorption (30,31). The
bioavailability of oral itraconazole also depends on the dosage form and the presence or
absence of food. Whereas food enhances itraconazole capsule dissolution and absorption
(32,33), oral itraconazole solution is already in the dissolved form and is better absorbed
when taken on an empty stomach (34). Also, the formulation of oral itraconazole solution
with cyclodextrin significantly improved its bioavailability (35,36).
   In one study, the bioavailability of itraconazole capsules increased from 40% with
fasting to 102% when administered with meals (32). In another study of 27 healthy
volunteers, a 200 mg, single oral dose itraconazole capsule was administered with or
without food. Pharmacokinetic parameters were analyzed for itraconazole and its active
metabolite hydroxyitraconazole. The AUC for itraconazole and its active metabolite
hydroxyitraconazole (3423 1154 ng.h/mL; 7978 2648 ng.h/mL, respectively) were
higher when itraconazole was administered with food as compared to fasting (2094
905 ng.h/mL; 5191         2489 ng.h/mL, respectively). The Cmax for itraconazole with
fasting was 59% that with food (140 65 ng/mL and 239 85 ng/mL, respectively),
and Cmax for hydroxyitraconazole with fasting was 72% that with food (286 101 ng/mL
and 397 103 ng/mL, respectively) (29).
   The absorption of oral itraconazole capsules is reduced when gastric acidity is decreased.
This typically occurs in patients treated with gastric acid suppressants (antacids, H2-recep-
tor antagonists, proton pump inhibitors). In hypochlorhydric patients, coadministration
of oral itraconazole capsules with an acidic beverage (e.g., cola) increased itraconazole
bioavailability (37,38). Following the administration of a single 100 mg dose of
itraconazole capsules with 325 mL of water or an acid cola beverage (pH 2.5), the AUC
for itraconazole was significantly higher with cola (2.02 1.41 µg·h/mL) than with water
(1.12      1.09 µg·h/mL) (p < 0.05). The Cmax of itraconazole was also significantly
higher with cola (0.31 0.18 µg/mL) than with water (0.14 0.9 µg/mL) (p < 0.05).
Additionally, the Tmax was longer with cola (3.38 0.79 h) than with water (2.56
0.62 h) (p < 0.05) (38).
    In contrast to itraconazole capsules, itraconazole oral solution does not require food
or acidic medium to increase its absorption. Significantly higher itraconazole and
hydroxyitraconazole AUC and Cmax, and shorter Tmax occur when itraconazole oral
solution is taken on an empty stomach rather than with food (30). Following adminis-
tration of oral itraconazole solution at a dose of 200 mg/d, respective mean itraconazole
and hydroxyitraconazole concentrations were 43 and 38% higher when itraconazole was
taken with food as compared to fasting (34). The AUC with a single 100 mg dose of
itraconazole oral solution was significantly higher when administered during fasting
(2379 1353 ng-h/mL) as compared to the fed state (1713 741 ng-h/mL). The Cmax
was also significantly higher in the fasting state (349 239 ng/mL) as compared to the
fed state (147 74 ng/mL) (p = 0.006). Additionally, the Tmax was significantly shorter
during fasting (1.7 0.5 h) as compared to the fed state (3.8 1.4 h) (p = 0.0001) (30).
   In summary, oral itraconazole capsules should be taken with a full meal for maximal
absorption. However, oral itraconazole solution is better absorbed when taken on an
empty stomach. Oral itraconazole solution provides an alternative to itraconazole cap-
sules in patients who have difficulty swallowing the capsule or in those whose oral intake
is restricted (29,33). The optimal serum itraconazole and hydroxyitraconazole concen-
trations are not known, however, itraconazole oral solution is associated with higher
200                                                    Part III/Influence of Food or Nutrients

serum drug concentrations compared to oral capsules (39). Administration of itraconazole
with cola enhances itraconazole capsule absorption in patients receiving acid suppression
therapy (37). Oral itraconazole solution should be taken on an empty stomach, at least 2 h
before or 2 h after a meal, to optimize oral absorption and bioavailability. Patients receiving
medications that alter gastric pH should take itraconazole oral capsules with a cola
2.7. Mebendazole
   Mebendazole is a broad-spectrum, anthelmintic agent available in oral chewable tab-
lets. Mebendazole is poorly absorbed form the GI tract, but its absorption is increased
when administered with food (3). When used for treatment of echinococcosis, systemic
bioavailability and intracystic mebendazole concentrations are essential to achieve thera-
peutic effect.
   Administration of mebendazole with a fatty meal to three healthy volunteers resulted
in an eightfold increase in plasma mebendazole concentrations. Plasma mebendazole
concentrations remained below 17 nmol/L in two subjects and a maximum concentration
of 17 nmol/L was achieved in the third subject. When the same dose was administered
with a standard breakfast (two slices of ham, two fried eggs, 10 g butter, jam, bread, and
coffee), plasma mebendazole concentrations rose within 2–4 h to 91 nmol/L, 112 nmol/L,
and 142 nmol/L in the three subjects, respectively (40). Mixing mebendazole with olive oil
also increased the drug’s bioavailability to a greater level than giving the tablets or
suspension with a standard breakfast (41). A wide variability in mebendazole absorption
was reported in patients treated for hydatid cysts. Although plasma mebendazole concen-
trations were higher when mebendazole was given with food, the difference was not
found statistically significant (42).
   When taken with food, higher plasma mebendazole concentrations are achieved. This
is a desirable effect in treatment of hydatid cysts. Mebendazole tablets can be chewed,
swallowed as a whole, or crushed and mixed with food (43).
2.8. Misoprostol
   Misoprostol is a prostaglandin E1 analog that is primarily used for preventing gastric
ulceration in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs).
Misoprostol is available in oral tablets. GI side effects such as diarrhea and abdominal
pain are common with misoprostol therapy. Diarrhea is dose-related and may sometimes
require discontinuation of misoprostol therapy. The incidence of diarrhea with 800 µg/d of
misoprostol in patients treated with NSAIDs ranges between 14 and 40%. Administration
of misoprostol after meals slows misoprostol absorption rate and thus reduces the fre-
quency of diarrhea (44).
   In a randomized, open-label, crossover study of 12 healthy volunteers, misoprostol
absorption was studied when taken with a high-fat meal or during fasting. Study results
showed food to decrease misoprostol absorption rate without significantly affecting the
amount and extent of misoprostol absorption. Food significantly increased misoprostol
Tmax (64 79 min) as compared to fasting (14 8 min) (p < 0.05). Food, however,
decreased misoprostol Cmax (303 176 pg/mL) as compared to fasting (811 317
pg/mL) (p < 0.05). Because achieving a rapid high Cmax of the active misoprostol
metabolite (misoprostol acid) may result in increased side effects (diarrhea and abdomi-
nal pain), these effects can be minimized when misoprostol is taken with food (45).
Chapter 10/Nutrients and Drug Effects                                                    201

   The effects of misoprostol on bowel motility were evaluated in a double-blind, cross-
over study of 12 healthy volunteers. Study results showed that orocecal transit time
(measured by H2 breath test following lactulose administration) was shortened by 57 and
18% when misoprostol was administered before and after meals, respectively. The mean
orocecal transit time was significantly shorter when misoprostol 400 µg was given before
meals compared to after meals (p < 0.001) and to placebo (p < 0.001). Although other
parameters such as stool frequency, fecal fat and bile acids, and fecal weight showed
differences between treatments, these differences were not found statistically signifi-
cant (46).
   In summary, administration of misoprostol before or after meals decreases the Cmax of
the active metabolite misoprostol acid without affecting misoprostol bioavailability (45).
Misoprostol should then be taken with food to reduce the incidence of diarrhea (44).
2.9. Nitrofurantoin
   Nitrofurantion is a broad-spectrum bactericidal agent that exerts its effects by possibly
interfering with bacterial carbohydrate metabolism (47,48) or cell-wall synthesis (49).
Nitrofurantoin is used for treatment of uncomplicated urinary tract infections caused by
susceptible microorganisms. Nitrofurantoin is available in different formulations includ-
ing nitrofurantoin monohydrate (75%) with macrocrystals (25%) in oral capsules
(Macrobid ), nitrofurantoin macrocrystalline oral capsules (Macrodantin ), and micro-
crystalline oral suspension (Furadantin ) (50–52). A tablet formulation was previously
manufactured but is no longer available.
   Oral nitrofurantoin is absorbed in the small intestines. Because serum nitrofurantoin
concentrations are usually low or undetectable in patients with normal renal function
(47,53,54), urinary nitrofurantoin levels are typically used to assess nitrofurantoin absorp-
tion (55). Macrocrystalline nitrofurantoin has slower dissolution and absorption rate
than nitrofurantoin monohydrate. Food, however, improves nitrofurantoin bioavailability
by about 40% (50) and substantially increases the duration of therapeutic nitrofurantoin
urine concentrations (47).
   The effects of food on nitrofurantoin absorption in macrocrystalline and microcrystal-
line tablets were evaluated in a study of four healthy volunteers. Nitrofurantoin 100 mg
single dose was administered either following an 8 h overnight fasting or immediately after
breakfast. Serial urinary specimens were collected to measure nitrofurantoin urine concen-
trations. Study results showed that food delayed nitrofurantoin absorption in the
macrocrystalline form but did not have a significant effect on the absorption rate of the
microcrystalline form. Food also resulted in increased maximum urine excretion rate of
macrocrystalline nitrofurantoin but did not have a significant effect on the excretion rate
of the microcrystalline form. Compared to fasting, food increased nitrofurantoin
bioavailability by an average of 30 and 80% of the microcrystalline and macrocrystalline
form, respectively (56).
   Another study compared the effects of food on the oral bioavailability of nitrofurantoin
in three different microcrystalline tablets, a macrocrystalline capsule, and an aqueous
microcrystalline suspension. The percent of a single 100 mg oral dose recovered in the
urine was significantly greater when administered with food compared to the fasting state
for the microcrystalline tablets (p < 0.05) and the macrocrystalline capsule (p < 0.05).
Food increased the bioavailability of the tablets and the macrocrystalline capsule by
23–400% and 85%, respectively. Although the bioavailability of the microcrystalline
202                                                   Part III/Influence of Food or Nutrients

suspension was also increased with food, this was not statistically significant. Compared
to fasting, food also significantly increased the mean duration of therapeutic urinary
concentrations of nitrofurantoin macrocrystalline capsule (p < 0.05). Compared to fast-
ing, food also increased the duration of therapeutic urinary concentrations of the micro-
crystalline suspension but the difference was not statistically significant. Nitrofurantoin
administration with food also improved the uniformity of nitrofurantoin absorption and
decreased the coefficients of variation. It was hypothesized that by decreasing the rate
of gastric emptying, food increases nitrofurantoin residence in the stomach, thereby
increasing drug dissolution that makes nitrofurantoin more readily absorbed in the
small intestines (57).
   In summary, food delays nitrofurantoin absorption thereby increasing its absorption
and reducing its peak plasma concentrations (52,57). Nitrofurantoin macrocrystals are
more slowly absorbed than the microcrystals (55,58). As such, nitrofurantoin macrocrystals
are better tolerated and are associated with less nausea and vomiting (59–61). Nitrofuran-
toin should be administered with food to enhance its absorption, increase the duration of
nitrofurantoin urinary concentrations, and improve GI tolerance (50).
2.10. Saquinavir
   Saquinavir is an antiretroviral agent used for treatment of HIV infection. Saquinavir
is available in oral capsules as saquinavir mesylate (Invirase ), and in soft capsules as
saquinavir (Fortovase ). The two dosage forms are not bioequivalent and cannot be used
interchangeably. Fortovase has better bioavailability as compared to Invirase. Following
administration of single 600 mg doses of saquinavir, the relative bioavailability of
Fortovase was 331% as compared to Invirase. Food, however, substantially increases
saquinavir absorption in either of the dosage forms (62,63). Administration of saquinavir
with food was reported to have increased saquinavir bioavailability by 1800% (64).
   In a study of six healthy volunteers who received saquinavir in a single 600 mg dose,
a 6.7-fold increase in AUC was reported when saquinavir was administered with food as
compared to fasting. Mean 24-h saquinavir AUC increased from 24 ng.h/mL with fasting
to 161 ng.h/mL following breakfast (1006 kcal, 57 g fat, 48 g protein, 60 g carbohydrate).
The 24-h AUC and Cmax were on average twofold higher following a higher calorie and
fat meal (943 kcal, 54 g fat) than a lower calorie and fat meal (355 kcal, 8 g fat) (62). In
another study of 12 healthy volunteers who received a single 800 mg dose of Fortovase, the
mean 12-h AUC increased from 167 ng.h/mL with fasting to 1120 ng.h/mL when saquinavir
was taken with breakfast (1006 kcal, 57 g fat, 48 g protein, 60 g carbohydrate) (63).
   In summary, food increases saquinavir bioavailability by increasing drug dissolution
and disintegration (65). As such, Fortovase and Invirase should be taken with food or
within 2 h after a meal (62,63). Owing to its improved absorption, Fortovase should be
used as the saquinavir formulation of choice of an antiretroviral regimen.

3.1. Ascorbic Acid and Iron
  Iron deficiency anemia can affect all age groups especially children and women of
childbearing age. There are two forms of iron in the diet including heme iron (from meat)
and non-heme iron (from cereals, fruits, and vegetables). Heme iron accounts for about
10–15% of iron intake when consuming a meat-rich diet, whereas most of the remaining
Chapter 10/Nutrients and Drug Effects                                                       203

dietary iron is in the non-heme form. Factors that increase (e.g., ascorbic acid) or decrease
(e.g., phytates) non-heme iron absorption do not, however, affect heme iron absorption
(66). On the other hand, ferrous iron (Fe2+) is better absorbed than ferric iron (Fe3+). Most
dietary iron is in the ferric state, but factors such as gastric acidity, dietary ascorbic acid,
and other reducing substances convert ferric iron to ferrous iron. When considering oral
iron supplements, the amount of iron absorbed depends on the type of iron salt used
(sulfate vs fumarate vs gluconate), iron dose administered, and body iron stores. For
instance, 10–35% of an oral iron dose is normally absorbed, whereas a greater amount
of iron is absorbed in patients with iron deficiency anemia (67).
   Iron absorption is significantly reduced by the presence of phytate in the diet. Phytates,
or hexaphosphates, are natural components of vegetables and cereals that bind iron in the
GI tract to form insoluble and unabsorbable compounds. Ascorbic acid inhibits iron
chelation to phytates and also reduces iron to the ferrous form, making it more available
for absorption (67). The amount of ascorbic acid needed to inhibit phytate binding to iron
depends on the amount of phytate present (68,69). The higher the phytate amount the
more ascorbic acid is required to reverse the inhibition. With meals containing no phytates,
ascorbic acid increases iron absorption by about 60% (70). When phytates were added
into wheat rolls at 2 mg, 25 mg, and 250 mg, iron absorption was inhibited by 18%, 64%,
and 82%, respectively. When 50 mg of ascorbic acid was given, absolute iron absorption
was highest when the rolls contained no phytates and was lowest when the rolls contained
250 mg of phytates. It is estimated that about 80 mg of ascorbic acid are needed to
counteract the effects of 25 mg of phytates, and a few hundred milligrams of ascorbic acid
are required to counteract the effects of 250 mg of phytates (71). The average North
American person consumes about 750 mg of phytates daily, although wide individual and
geographical variations exist (72).
   Iron absorption was increased two- to threefold when 50 mg of ascorbic acid were
added twice daily to each meal (66–69). The first 50–100 mg doses of ascorbic acid
appear to have the most significant effects on iron absorption. Higher doses have little
additional effects (70). Administration of ascorbic acid at doses of 500 mg twice daily
after meals for 2 mo significantly improved iron status in strict vegetarians (73). How-
ever, there was no significant effect on serum ferritin levels when higher ascorbic acid
doses of 1 g twice daily were given to adults consuming a well-balanced diet. The lack
of significant response with high ascorbic acid doses may indicate that iron reserves are
maintained under tight control regardless of the mechanisms that enhance iron
bioavailability (74). Also, ascorbic acid supplementation may have little effect on
improving iron absorption in well-nourished, non-iron-depleted subjects.
   Ascorbic acid effects on iron retention were also evaluated in premenopausal women
following induction of iron depletion by a low-iron diet and phlebotomy. Women in this
study consumed a low-iron diet that provided 5 mg of elemental iron per 2000 calories for
67–88 d. At the end of the low-iron diet period, subjects were divided into three groups to
receive a diet containing either 13.7 mg of iron per 2000 calories, or supplemental ascor-
bic acid 500 mg three times daily with meals, or a placebo supplement for 5.5 wk. Study
results showed significant improvement in apparent iron absorption (defined as the dif-
ference between dietary and fecal iron) with ascorbic acid supplementation compared to
placebo. Blood analysis at the end of 5 wk showed ascorbic acid to have also improved
hemoglobin, serum iron concentration, and erythrocyte protoporphyrins. Ascorbic acid
204                                                   Part III/Influence of Food or Nutrients

had no effect on improving serum ferritin, transferrin saturation, hematocrit, or total iron-
binding capacity (75).
   Ascorbic acid effect on iron absorption was also reported in children. In a study that
evaluated ascorbic acid effect on iron absorption in 54 preschool Indian children with iron
deficiency, ascorbic acid supplementation at a dose of 100 mg twice daily given with
meals for 60 d resulted in significant improvement in hemoglobin (p < 0.001) and red cell
morphology as compared with placebo (p < 0.01) (76). In another study of 65 Chinese
children with mild iron deficiency anemia who were consuming a predominantly veg-
etarian diet, daily ascorbic acid supplementation at 50 mg, 100mg, and 150 mg had nearly
the same effects on improving iron status (77).
   The fraction of iron in ferritin and ferric hydroxide that enters the non-heme dietary
iron is also influenced by diet composition. One study compared the absorption of iron
from ferritin iron and ferric hydroxide in 35 multiparous women. When administered in
water, the geometric mean iron absorption was 0.7 and 2.4% from ferritin iron and ferric
hydroxide, respectively. With the presence of 100 mg ascorbic acid in dietary maize
porridge, iron absorption increased to 12.1% for ferritin and 10.5% for ferric hydroxide,
compared to 0.4% for both compounds with maize porridge without ascorbic acid (78).
   Ascorbic acid in fruit juices and vegetables is as effective as equal amounts of
synthetic ascorbic acid in enhancing iron absorption (69). In a study that evaluated the
effect of fruit and fruit juices on iron absorption from a rice diet containing 0.4 mg of
iron, juices of citrus fruits with higher ascorbic acid content resulted in higher amounts
of iron absorbed (79).
   Iron supplements are commercially available in different salt forms (gluconate, fuma-
rate, sulfate) providing different elemental iron amounts (80). Iron sulfate is the most
widely prescribed oral iron supplement usually given in one to three daily doses.
Coadministration of 100–200 mg/d of ascorbic acid with iron supplements enhances iron
absorption especially in anemic patients (67). Patients who poorly absorb iron, such as
those with gastrectomy, would most benefit from ascorbic acid supplementation during
oral iron therapy (81). Various combinations of commercial iron and ascorbic acid for-
mulations can also be found such as Fero-Grad-500 (timed-release tablet containing
ferrous sulfate 105 mg with sodium ascorbate 500 mg), Vitelle Irospan (timed-release
tablet and capsule containing ferrous sulfate exsiccated 65 mg with ascorbic acid 150 mg),
Hemaspan (containing ferrous fumarate 110 mg with ascorbic acid 200 mg), and Cevi-
Fer (timed-release capsule containing ferrous fumarate 20 mg with ascorbic acid 300
mg). Slow-release formulations of iron may result in portions of the dose bypassing the
intestinal sites of absorption.

4.1. Pyridoxine and Isoniazid
   Isoniazid is an antimycobacterial agent used for treatment and prophylaxis of Myco-
bacterium tuberculosis infections. Peripheral neuropathy is the most common side effect
of isoniazid therapy (82). Peripheral neuropathy is dose-related and occurs mainly in
“slow-acetylators,” chronic alcoholics, malnourished, uremic, and diabetic patients. Signs
and symptoms of peripheral neuropathy include paresthesias of the feet and hands, muscle
Chapter 10/Nutrients and Drug Effects                                                  205

weakness, and diminished or exaggerated reflexes. The mechanism of isoniazid-induced
peripheral neuropathy is likely related to isoniazid-induced pyridoxine deficiency or to
isoniazid-blocking effect of pyridoxal phosphate synthesis by inhibition of pyridoxine
kinase activity (83,84). Vitamin B6 occurs in the body as pyridoxine, pyridoxal, and
pyridoxamine (85). Pyridoxine kinase is the enzyme that converts pyridoxal to pyridoxal
phosphate (83,84). Pyridoxal phosphate is the active byproduct of pyridoxal metabolism
that acts as a coenzyme in the metabolism of neurotransmitters. Reduced pyridoxal
phosphate availability during isoniazid therapy is believed to cause reduction in neu-
rotransmitter synthesis that eventually leads to peripheral neuropathy (84).
   The incidence of peripheral neuropathy correlates with the isoniazid dose and the
presence or absence of patient-specific factors. Peripheral neuropathy occurs in about
1–2% of patients treated with the usual isoniazid doses of 3–5 mg/kg/d (82). The
incidence of peripheral neuropathy increases to 40% with isoniazid doses of 20 mg/kg/d
(83). In malnourished patients, even low isoniazid doses of 4–6 mg/kg/d may cause periph-
eral neuropathy in up to 20% of patients (84). Peripheral neuropathy does not usually
appear until 6 mo of isoniazid therapy (82), but could appear earlier in malnourished
patients or those with preexisting pyridoxine deficiency (86).
   It is a common practice to supplement pyridoxine at doses of 15–50 mg/d during the
course of isoniazid therapy. Higher pyridoxine doses of 100 mg/d are required in patients
treated with hemodialysis. Increased pyridoxine requirement during hemodialysis is
likely resulting from reduced pyridoxine metabolism to active pyridoxal phosphate and
increased dialysis clearance of pyridoxal phosphate (87). Pyridoxine has also been used
to prevent or treat isoniazid-induced psychosis (85,88) and seizures (89,90). Seizures are
the major toxic reactions of isoniazid overdose (82). In case of isoniazid overdose, intra-
venous pyridoxine doses of 1 g for each 1 g of isoniazid dose ingested were used without
evidence of pyridoxine toxicity (90,91).
   In summary, peripheral neuropathy rarely occurs in well-nourished patients treated
with isoniazid doses up to 5 mg/kg/d (92). Adult patients treated with isoniazid, espe-
cially those at high-risk for peripheral neuropathy, should receive prophylactic oral
pyridoxine at doses of 50 mg/d (82). Although high pyridoxine doses can possibly reduce
isoniazid activity (93) or even cause neuropathy (94), doses of 100–200 mg/d have been
safely used to treat isoniazid-induced peripheral neuropathy (84,93). The practice of
avoiding pyridoxine prophylaxis in children receiving isoniazid should be discouraged
especially in malnourished children (95). Children treated with isoniazid may be supple-
mented with oral pyridoxine at dose of 1–2 mg/kg/d (96).
4.2. Folic Acid and Methotrexate
   Methotrexate is an antineoplastic antimetabolite used for treatment of certain cancers.
Methotrexate is also used for treatment of psoriasis and rheumatoid arthritis (RA). Meth-
otrexate use in RA is based on its anti-inflammatory, immunosuppressive, and
antiproliferative effects. A low-dose methotrexate of 5–25 mg/wk is usually used for
short- and long-term treatment of adults with RA (97,98). Higher doses are exceptionally
used when efficacy is not achieved at low doses. Significant toxicities, especially bone
marrow suppression, occur at methotrexate doses exceeding 20 mg/wk (99). Dose-
related hematological, GI, hepatic, and pulmonary toxicities frequently lead to cessa-
tion of methotrexate therapy (100,101).
206                                                    Part III/Influence of Food or Nutrients

   Methotrexate is structurally similar to folic acid. Methotrexate inhibits the dihy-
drofolate reductase enzyme that reduces folic acid to tetrahydrofolic acid. This results in
decreased intracellular levels of reduced folates and inhibition of DNA synthesis and
cellular replication (100,101). The resultant folate depletion and inhibition of folate-
dependent enzymes contribute to methotrexate toxicities in nontarget tissues. Diarrhea,
stomatitis, and leukopenia are manifestations of methotrexate toxicity that mimic the
symptoms of folic acid deficiency (102). Thus, adequate folate supplementation is cru-
cial to reduce methotrexate toxicity.
   Leucovorin (folinic acid) is a chemically active reduced folate derivative that is clini-
cally used as a folate rescue to counteract methotrexate toxicity. Low oral doses of
leucovorin at 2.5-5 mg/wk are used in combination with low-dose methotrexate (103).
Low leucovorin doses reduce methotrexate toxicity without altering its efficacy. How-
ever, higher leucovorin doses (45 mg/wk) may counteract methotrexate efficacy and
result in worsening of RA (104). As such, folic acid has been investigated as a possible
substitute for leucovorin. Compared to methotrexate, folic acid has a lower affinity to the
dihydrofolate reductase enzyme. This gives folic acid the advantage of reducing meth-
otrexate toxicity without counteracting its efficacy.
   Low plasma and erythrocyte folate and high homocysteine levels were reported in
patients treated with methotrexate without folate supplementation (105,106). Plasma
homocysteine levels decreased following folic acid or folinic acid supplementation (106).
Reducing homocysteine levels may have a long-term cardiovascular protective effect
because hyperhomocysteinemia may be a risk factor for cardiovascular disease (107).
   The optimal dose and timing of folic acid supplementation in relation to methotrexate
therapy are still debatable. Although weekly folic acid doses of 1 mg (108) and 5 mg (100)
were shown to reduce low-dose methotrexate toxicity, higher doses were suggested to
sufficiently prevent methotrexate toxicity (109). The effects of folic acid on reducing
low-dose methotrexate toxicity were evaluated in a double-blind, placebo controlled trial
of 79 patients with RA. Oral folic acid doses of either 1 mg/d (5 mg/wk) or 5.5 mg/d
(27.5 mg/wk) were given 5 d a week on days not coinciding with methotrexate admin-
istration. Study results showed that either folic acid dose resulted in lower toxicity scores
compared to placebo (p < 0.001). Also, neither folic acid dose interfered with methotr-
exate efficacy as assessed by joint indices and grip strengths (101). However, results of
another study using folic acid doses at 5 mg/d for 13 consecutive days along with weekly
intramuscular methotrexate showed alterations in methotrexate pharmacokinetics. There
was a significant decrease in plasma methotrexate concentrations and increased total
methotrexate clearance. The investigators concluded that decreased plasma methotrex-
ate concentrations were possibly due to folic acid-induced increased cellular methotrex-
ate uptake (110). Based on these results, the question remains about the optimal folic acid
dose that reduces methotrexate toxicity without interfering with its efficacy.
   A meta-analysis of seven double-blind randomized controlled studies was conducted
to evaluate the effects of folic acid or folinic acid on the toxicity of low-dose methotrexate
(< 20 mg/wk) in patients with RA. Results of the meta-analysis showed a 79% reduction
in methotrexate-induced mucosal and GI toxicity with folic acid supplementation. A
clinically but not statistically significant 42% reduction of the same side effects was seen
with folinic acid. Similar effects were also achieved with low- and high-dose folic acid
(1-27.5 mg/wk) or folinic acid (1-20 mg/wk). However, high folinic acid doses were
Chapter 10/Nutrients and Drug Effects                                                    207

associated with increased tender and swollen joint count, a possible indication of decreased
response to methotrexate (100). The protective effects of folic acid reported in the meta-
analysis (100) were not, however, replicated in a later individual study. In a 48-wk
multicenter, randomized, double-blind, placebo-controlled study, folic acid at 1 mg/d
and folinic acid at 2.5 mg/wk reduced the incidence of elevated liver enzymes without
affecting the incidence, severity, or duration of other toxicities including mucosal and GI
side effects (112).
   Based on available data, folic acid supplementation appears to reduce low-dose meth-
otrexate toxicity (109) and results in less frequent interruption of methotrexate therapy
(112). Relying on dietary folic acid intake alone may not be sufficient to prevent methotr-
exate toxicity (113). Because folic acid supplements are safe, effective, and less expen-
sive than folinic acid (114), weekly oral folic acid supplementation given on
non-methotrexate days appears an appropriate substitute to leucovorin. Although there
is no unanimity on the optimal folic acid dose, clinical studies reported weekly folic acid
doses of 1 mg, 5 mg, and 27.5 mg to be safe and effective in reducing low-dose methotr-
exate toxicity (100). Baseline patient folate status, methotrexate dose, and duration of
methotrexate therapy appear to play a role in determining the optimal protective dose of
folic acid. Reports of possible liver protective effects of folic acid are encouraging and
require further exploration (115).

4.3. Folic Acid and Fluorouracil
   Fluorouracil (5-FU) is a fluorinated pyrimidine antineoplastic antimetabolite used in
the palliative management of colorectal, stomach, pancreatic, breast, ovarian, and head
and neck cancers. 5-FU exerts its effects primarily through its active metabolite
fluorodeoxyuridine monophosphate that inhibits thymidylate synthase, a key enzyme in
pyrimidine synthesis. Leucovorin, a modulator of 5-FU activity, is typically adminis-
tered intravenously in combination with 5-FU to enhance 5-FU activity. Leucovorin
enhances thymidylate synthase inhibition through increasing the intracellular pool of
folates that stabilizes the thymidylate synthase–fluorodeoxyuridine monophosphate
complex (116,117). Because reduced folate metabolites enhance 5-FU antitumor activ-
ity, folic acid has been proposed as an alternative to leucovorin as long as it generates the
same plasma metabolite levels. Animal studies have shown potential modulating effects
for folic acid in mice with lymphocytic leukemia treated with 5-FU (118). However,
human studies evaluating the role of folic acid as a possible modulator of 5-FU activity
are limited.
   A crossover, randomized pharmacokinetic study evaluated the metabolism of folic
acid and its ability to yield reduced folates. The study included 10 adult volunteers who
were divided into two groups. One group received folic acid at doses of 25 mg/m2 and
the other group received 125 mg/m2. After a 2-wk washout period, the same group
received the same folic acid dose by the alternative route. Serial blood samples were
collected over 24 h following folic acid administration. Plasma samples were analyzed
for folic acid and for reduced folate metabolite concentrations. Study results showed a
twofold increase in plasma-reduced folate concentrations with the higher oral folic acid
dose as compared to the lower dose. In comparison with other studies using leucovorin,
the same reduced folate metabolites were generated following folic acid administration.
Folic acid at 125 mg/m2 was at least as effective as leucovorin in increasing plasma-
208                                                    Part III/Influence of Food or Nutrients

reduced folate concentrations. However, folic acid metabolites accumulated at a slower
rate and persisted longer than leucovorin metabolites. Based on these results and consid-
ering the short half-life of 5-FU, the study concluded that folic acid offers a potential
therapeutic alternative to leucovorin in modulating 5-FU efficacy. It was also concluded
that giving folic acid 4–6 h before 5-FU allows enough time for effective accumulation
of reduced folate metabolites (119).
   However, a clinical study combining 5-FU and high-dose folic acid yielded disap-
pointing results. The study included 22 patients with metastatic colorectal cancer who
received a weekly dose of 5-FU 600 mg/m2 (maximum 1 g) administered 1 h after an
intravenous folic acid dose. The starting folic acid dose was 40 mg/m2 escalated based
on tolerance to the maximum dose of 140 mg/m2. Study results showed a low response
rate and severe toxicities with the combination therapy of folic acid and 5-FU, as com-
pared to 5-FU alone. Only four patients had partial responses for a mean duration of 4 mo,
but no patient had complete response. Severe diarrhea requiring hospitalization was
reported in 12 patients and also caused 3 patients to drop out of the study. Two patients
developed leukopenia and died later from sepsis. The study concluded that the use of folic
acid with 5-FU could not be justified and that further studies were still needed. There was
no clear explanation for the low response rate and high toxicities encountered in this
study. The 5-FU dose was within the usual recommended dose. Mean serum folate
concentrations at 1 h after folic acid administration were 11 nmol/L higher than the in
vitro optimal levels for stabilization of the thymidylate synthase–fluorodeoxyuridine
monophosphate complex. However, interpretation of these levels is difficult because
serum folate levels do not necessarily correlate with intracellular folate concentrations.
Also, it was unknown whether folic acid or the folic acid dose could have contributed to
these effects, or even if patients with colorectal cancer are more sensitive to the combi-
nation therapy (120). For instance, severe GI toxicities (e.g., stomatitis and diarrhea) are
more commonly seen in patients with colorectal cancer who are treated with leucovorin
and 5-FU, as compared to 5-FU alone. For safety reasons, it is generally recommended
that patients who develop GI toxicity should not be initiated or continued on leucovorin
therapy with 5-FU, and that patients should be monitored closely until diarrhea resolves (121).
   At present, intravenous leucovorin remains the agent of choice for modulation of 5-FU
effect. The safety, efficacy, optimal dose, and dosing schedule for folic acid as a modulator
of 5-FU activity remain unknown. Studies comparing leucovorin to folic acid are needed
before folic acid can be recommended as a safe and effective modulator of 5-FU effect
in the treatment of cancer.
5.1. Plant Stanols and Statins
   The management of dyslipidemia combines drug therapy and lifestyle modifications.
  -Hydroxy- -methylglutaryl-CoA reductase inhibitors (“statins”) are the most widely
prescribed agents to lower low-density lipoprotein (LDL) cholesterol. Besides reducing
cholesterol intake, an alternate or adjunct approach in managing hypercholesterolemia is
inhibiting cholesterol absorption with dietary inclusion of plant sterols and stanols. Plant
sterols and stanols block dietary and biliary cholesterol absorption in the small intestines
and cause reduction of serum cholesterol and LDL levels (122,123).
Chapter 10/Nutrients and Drug Effects                                                      209

    Plant sterols (phytosterols) are naturally occurring plant constituents. They are C-28
(campesterol) and C-29 (sitosterol, stigmasterol) sterols. They are mainly found in edible
oils, nuts, and seeds. Plant stanols are saturated derivatives of plant sterols with sitostanol
being the most common stanol. Sitostanol is found mainly in wood pulp, tall oil, and to
a lesser extent in soybean oil.
    Western diets provide about 100–300 mg/d of plant sterols and 20–50 mg/d of plant
stanols. Plant stanols and sterols have been incorporated into various food products
including margarine and salad dressing and are more used in Europe than in the United
States. Although plant stanols and sterols have shown to be equally effective in reducing
cholesterol levels (122), the compounds have inherent differences. For instance, plant
stanols are preferable over plant sterols because they are relatively unabsorbed from the
GI tract. Although plant sterols are poorly absorbed, daily sterols intake of 3.24 g increase
serum sitosterol and campesterol by 40 and 70%, respectively. Because of concerns that
plant sterols and their byproducts may initiate the development of atherosclerosis, plant
stanols appear safer substances especially during long-term consumption (124).
    Plant stanols have been used in adjunct therapies with statins to manage hypercholes-
terolemia. Because statins inhibit cholesterol synthesis and stanols block cholesterol
absorption, an additive effect of combining the two agents would be anticipated to further
lower serum cholesterol levels. The combined effects of statins and plant stanols are
equivalent to a one- to twofold increase in statin dose (125). A double-blind, placebo-
controlled study evaluated the effects of adding dietary plant stanol esters (esterified
plant stanols) to statin therapy. One-hundred-sixty-seven adults with serum LDL-choles-
terol concentrations of 130 mg/dL or higher and total cholesterol concentrations of 350
mg/dL or lower who had been receiving a stable dose of a statin for at least 90 d were
included in the study. Subjects were randomized to receive either dietary canola oil
based-spread in three servings that provided 5.1 g/d of plant stanol ester (equivalent of
3 g/d of plant stanols) or placebo for a period of 8 wk. Study results showed plant stanols
in combination with statins significantly reduced serum total cholesterol (12 vs 5%, p
< 0.0001) and LDL levels (17 vs 7%, p < 0.0001), as compared to placebo. There were
no changes in serum triglyceride or high-density lipoprotein concentrations. Plant stanols
were well tolerated (126).
    When considering statin therapy alone or in combination with stanols, doubling the
statin dose would reduce serum LDL levels by an additional 6%, whereas a 10% reduc-
tion in LDL levels is achieved when statins are combined with stanols. Also, doubling the
statin dose carries the risk of hepatic and muscle toxicity. As such, adding plant stanols
to statin therapy appears a safer alternative (125,126). However, a possible limiting factor
to stanol efficacy alone is related to the liver upregulation of its LDL receptor activity to
increase LDL synthesis in response to decreased cholesterol levels in liver cells (127).
The magnitude of this compensatory effect remains unknown.
    A commercial product containing plant stanol esters (Benecol ) is available in spreads
and softgels. It is usually taken with meals in two to three daily servings and appears to
be well tolerated. However, the overall efficacy of plant stanols and sterols on lowering
serum cholesterol remains modest especially with the associated compensatory increase
in liver cholesterol synthesis (127). Also, the relatively high cost of plant stanol and sterol
products and the need to consume them several times daily makes them less appealing
to the consumer.
Table 1
Summary of Relevant Drug–Nutrient Interactions That May Optimize Drug Effect
                                                                 Relevant Effects
   Drug        Diet/Nutrient    Proposed Mechanism                of Interaction                       Recommendations
Albendazole     Fatty meal      Increased solubility        Increased plasma and tissue       Should be taken with food when
                                   and absorption              drug concentrations            treating systemic infections
                                                            Enhanced therapeutic effect
Atovaquone      Fatty meal      Increased solubility        Increased plasma concentrations   Should be taken with food
                                   and absorption           Enhanced therapeutic
Cefuroxime Meals, Milk          Increased absorption        Increased plasma concentrations   Preferably taken with food or milk
axetil (tablets)                   with decreased           However, bactericidal
                                   gastric pH                  activity not affected
Fluorouracil    Folic acid      Increased levels            Possible reduction of 5-FU        Efficacy and safety not established
(5-FU)                             of reduced                 toxicity and modulation
                                   folate metabolites         of 5-FU activity

                                                                                                                                                  Part III/Influence of Food or Nutrients
Griseofulvin    Fatty meal      Increased disintegration    Increased plasma concentrations   Should be taken with food
                                   and absorption           Enhanced therapeutic effect
Iron            Ascorbic acid   Inhibition of iron          Increased iron absorption         Coadminister ascorbic acid
                                   chelation to phytates                                        (100–200 mg/d) with iron in
                                Reduction of iron                                               patients who are poor absorbers
                                  to the ferrous form
Isoniazid       Pyridoxine      Increased pyridoxal         Prevention of isoniazid-induced   Coadminister prophylactic pyridoxine
                                   phosphate availability      peripheral neuropathy             to adults (50 mg/d) and children
                                                                                                (1–2 mg/kg/d) receiving isoniazid
Isotretinoin    Meals           Increased solubility        Increased plasma concentrations   Should be taken with food
                                   and absorption           Enhanced therapeutic effect
Table 1 (continued)

                                                                                                                                              Chapter 10/Nutrients and Drug Effects
                                                                 Relevant Effects
   Drug        Diet/Nutrient      Proposed Mechanism              of Interaction                       Recommendations

Itraconazole      Meals, acidic    Increased solubility      Increased plasma concentrations   Should be taken with food or an acidic
(capsules)          beverages         and absorption         Enhanced therapeutic effect           beverage (e.g., cola)
                                      in acidic medium                                         Itraconazole oral solution should
                                                                                                   be taken on empty stomach
Mebendazole       Meals            Increased absorption      Increased target                  Should be taken with food when
                                                                drug concentrations              treating systemic infections
                                                             Enhanced therapeutic effect
Methotrexate      Folic acid       Increased levels          Reduced low-dose                  Weekly folic acid doses of 1 mg,
                                   of reduced folate           methotrexate toxicity             5 mg, and 27.5 mg
                                      metabolites              in the treatment                  have been used with low-dose
                                                               of rheumatoid arthritis           methotrexate regimens
Misoprostol       Meals            Reduced absorption rate   Reduced frequency                 Should be taken with food
                                   Reduced peak                of diarrhea
                                     plasma concentrations
Nitrofurantoin    Meals            Increased dissolution     Increased duration                Should be taken with food
                                      and absorption            of urinary concentrations,
                                                             Reduced peak
                                                                plasma concentrations
                                                             Improved gastrointestinal
Saquinavir        Meals            Increased dissolution,    Increased therapeutic effect      Should be taken with food or within
                                      disintegration                                             2 h after a meal
                                      and absorption
Statins           Plant Stanols    Blockage                  Reduced serum cholesterol         Use stanols two to three times a day in diet
                                   of cholesterol              and low-density                   or as adjunct to lipid-lowering therapy

                                      absorption                lipoprotein levels
212                                                             Part III/Influence of Food or Nutrients

   Selective cholesterol absorption inhibitors have been under investigation. Ezetimibe
(Zetia ) is a selective cholesterol absorption inhibitor that recently became available.
Ezetimibe has been shown to reduce LDL cholesterol levels by about 17% as a
monotherapy agent (128), and by 25% when combined with statins (129). Ezetimibe
offers the advantages of significantly reducing LDL levels with a once daily dose of 10 mg
taken without regard to meal or time of the day (130).
   DNIs can cause increased or decreased drug effect. Beneficial DNIs either enhance
therapeutic drug effect or reduce drug toxicity. Clinicians should be aware of these inter-
actions and should counsel patients about the appropriate nutrient intake to improve the
safety and efficacy of drug therapy.

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Chapter 11 / Dietary Supplements and Medication                                            217

   11            Dietary Supplement Interactions
                 With Medication

                 Jeffrey J. Mucksavage
                 and Lingtak-Neander Chan

   Routine, self-initiated supplementation with nutritional, herbal, and other related prod-
ucts is common among individuals in the Western world (1,2). Among the most likely
users of dietary supplements include middle-aged Caucasian women and elderly with
preexisting medical conditions or chronic diseases often requiring medication. There-
fore, the potential for drug–nutrient interactions (DNIs) is high and the resulting adverse
reactions can be serious. Given the recent tragedies and reports implicating the use of
dietary supplements (3–11), the potential risks and adverse effects of these products,
ostensibly for health benefit, cannot be underestimated.
   This chapter discusses the topic of dietary supplements and their interactions with
commonly used prescription medications. It defines dietary supplements, describes the
interactions of dietary supplements with prescription drugs focusing on some of the most
commonly used supplements, describes the limitations in characterizing these interac-
tions, and offers suggestions for clinicians to help identify, monitor, and avoid these
interactions. It addresses the effects and mechanisms of nutrient-containing, herbal-
containing, and non-nutrient/nonherbal-containing dietary supplements on the pharma-
cokinetics and pharmacodynamics of prescription medications. Following a general
discussion, the focus is on the five most popular selling non-nutrient, dietary supplement
ingredients (ginseng, St. John’s wort [SJW], garlic, ginkgo, and echinacea) and vitamin
   The ideal and the most organized way to approach DNIs would be to neatly charac-
terize these supplement interactions with prescription medications into the four mecha-
nism-based categories (Table 1). However, the complexity of products, paucity of clinical
trials, void of product standardization, and lack of product dose reproducibility limits the
ability to accurately delineate, characterize, and quantify these interactions (12). The reader
should keep in mind that this chapter is not intended to serve as an all exhaustive review

                             From: Handbook of Drug–Nutrient Interactions
            Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
218                                                  Part III / Influence of Food or Nutrients

                      Table 1
                      Mechanism-Based Interactions
                      Category              Description
                      Type I             Ex vivo bioinactivation
                      Type II            Absorption
                        IIA              Metabolism
                        IIB              Transport
                        IIC              Complexation
                      Type III           Physiologic disposition
                      Type IV            Elimination
                         From ref. 12.

of potential herb–drug interactions, but is more intended to serve as a reference for the
mechanism of major herb–drug and vitamin–drug interactions that are currently the most
clearly studied and defined.

1.1. Definition of Dietary Supplements
   In 1994, Congress passed the Dietary Supplement Health and Education Act (DSHEA)
which amended the Food, Drug, and Cosmetic Act, changing the framework for regulat-
ing dietary supplements as a unique entity. DSHEA defines a dietary supplement as (13):
  ..a product (other than tobacco) intended to supplement the diet that bears or contains
  one or more of the following dietary ingredients: a vitamin, mineral, herbs or other
  botanicals, amino acids, a dietary substance used by man to supplement the diet by
  increasing the total dietary intake; or a concentrate, metabolite, constituent, extract,
  or combination of any ingredient described above; and intended for ingestion in the
  form of a capsule, powder, softgel, or gelcap, and not represented as a conventional
  food or as sole item of a meal or diet.
   The stimulus for these changes was the thought that the people of the United States
recognized that these products may benefit their health. Although the intent was to
increase availability of products and information about those products, in effect, this act
eliminated the premarket safety evaluations for dietary supplements that apply to food
ingredients. Under this act and the current regulations, dietary supplements are not
required to undergo the rigorous testing for safety and efficacy before being marketed,
including identification of interactions, which is currently required of all prescription
medications. Also, the Food and Drug Administration (FDA) does not monitor the manu-
facturing practices of the companies marketing these products, and leaves the manufac-
turer responsible for data supporting any product claims in the labeling. The FDA does
not generally review statements made on the labeling of dietary supplements. Thus, the
DSHEA places the burden of proof on the government if it wishes to take regulatory
action against a supplement. The government must show that the supplement presents a
“significant or unreasonable risk of illness or injury” under the conditions recommended
or suggested in labeling (or under ordinary conditions of use if the labeling is silent).
DSHEA’s regulatory framework, unlike the system involved in drug regulation requiring
extensive premarketing evaluation of safety and efficacy, is primarily a “postmarket”
Chapter 11 / Dietary Supplements and Medication                                          219

program similar to the bulk of food regulation. Whether the recent tragic events involving
a number of dietary supplements will change the government’s regulatory approach
remains to be determined. Regulations for Good Manufacturing Practices of dietary
supplements have been recently proposed by the FDA (14).

1.2. Prevalence of Dietary Supplement Use
   As a result of the DSHEA, use and sales for dietary supplements in the United States
have increased dramatically. The Vitamins and Lifestyle study found that 75% of the
study cohort (35,000 men and 40,000 women in Washington State) had used at least one
dietary supplement in the last 10 years (1). Similarly, a survey conducted in 2000 involv-
ing 1183 respondents from the members of the Dutch Health Care Consumer Panel
revealed that at least 36% of the respondents took echinacea-containing supplements and
at least 52% took multivitamin and mineral supplements (2). In 1996, more than $6.5
billion was spent in the United States on dietary supplements (15). Total sales of these
products grew to more than $12 billion in 1998 and more recently this sum has grown to
more than $17.6 billion in 2001 in the United States (15,16). This figure accounts for
products containing vitamins, minerals, and other nutrients, to herbal products, sport
products, and specialty type products. Considering the results of a survey of Americans
conducted in 1999 that estimated that 9.6% of those studied, or more than 19 million
Americans, have turned to herbal medicine as a form of alternative medicine second only
to prayer, herbal products have a strong foothold for use in the United States (17). A
separate random survey of the noninstitutionalized population in the United States found
that approx 81% of participants used at least one prescription or over-the-counter medi-
cation in the previous week, and 16% of patients using prescription products also reported
using one or more herbal products or supplements (18). A recent survey conducted in 979
preoperative patients undergoing anesthesia showed that 17.4% reported current use of
herbal or selected dietary supplements (19). In reality, the actual number of patients using
dietary supplements may be underrepresented in these studies because not all patients
readily report to their physicians and other health care providers the use of these products.
Additionally, patients tend to underreport use of these products on written questionnaires
(20). Because such a large number of people are using herbal supplementation concomi-
tantly with prescription medication, the stage is set for significant and potentially danger-
ous interactions that may result from the use of these products simultaneously.

2.1. Confounding Issues With Dietary Supplements
   A potential problem for documenting interactions with dietary supplements and pre-
scription products is that the labeling of these products may not reflect the actual ingre-
dients present in the formulation. A wide array of compounds were found in the products
ranging from undeclared pharmaceuticals such as ephedrine and chlorpheniramine, to
toxic levels of heavy metals including lead and arsenic in some Asian patent medicinal
products sold in California (21). A review of 25 commercially available ginseng prepa-
rations found that although the labeled plant products were in fact present in the prepa-
ration, the concentrations of these compounds, however, differed from labeled amounts
(22). Also, a study of steroid-containing supplements found a disparity between the
220                                                   Part III / Influence of Food or Nutrients

labeled amount of steroids in the product and the actual quantity within it. One product
tested even contained testosterone, which is a class II controlled substance in the United
States (23). Not only do potential safety concerns exist when undisclosed drugs appear
in these products, but questionable purity and accuracy of labeling further confound
health care professionals, making their jobs more difficult in identifying and managing
potential interactions and adverse reactions associated with FDA-approved medications.
For example, a documented interaction between a supplement product and a medication
may be the result of a poorly formulated product rather than to the labeled active ingre-
dient per se. These issues are unlikely to be changed unless a significant revision or
amendment to DSHEA takes place.

2.2. Type of Data Available
    Because of the difficulties associated with studying herbal products, the literature
currently available to classify these interactions is quite limited and consists mainly of
case reports and anecdotal evidence. Like other types of drug–drug interactions, dietary
supplements may act as the precipitant agent and thus can affect the pharmacokinetics
and pharmacodynamics of prescription medications (object drugs). From the pharmaco-
kinetic standpoint, dietary supplements can have profound effects on the absorption,
distribution, elimination or clearance of the object drug through metabolic inhibition or
induction of specific enzymes and transporters. A considerable number of herbs and
supplements have been identified as potent inhibitors of the cytochrome P450 (CYP)
enzyme system, the most important phase I enzyme family responsible for the biotrans-
formation of many biogenic amines, steroids, cholesterol, and most prescription drugs
used in the United States (24). Some herbs and nutrient supplements also affect the
functions of cell membrane transporters. For example, SJW induces intestinal P-glyco-
protein (P-gp) (25,26). P-gp is an adenosine-5'triphospate (ATP)-dependent efflux pump
encoded by the multidrug resistant gene-1, which is located on chromosome 7. It belongs
to the ATP-binding cassette transporter family and is highly expressed in the gastrointes-
tinal tract, renal tubule, the blood–brain barrier, the liver, and several other tissues. P-gp
is particularly highly expressed and functionally active in the intestinal epithelial tissues.
Its primary function involves active transport of specific xenobiotics, drugs, chemicals,
or even certain food substances that have already been absorbed by the epithelial cells
back into the gut lumen (27,28). This is likely an intrinsic defense mechanism of the
human body to decrease the exposure to xenobiotics (in other words, “foreign” com-
pounds). Many drugs, especially those with low oral bioavailability, are substrates of P-
gp and modulation of intestinal P-gp activity can directly alter their absorption.
Cyclosporine, digoxin, most dihydropyridine calcium channel blockers, and a number of
protease inhibitors are examples of P-gp substrates. Induction of P-gp by SJW can de-
crease the systemic absorption of digoxin leading to subtherapeutic serum concentrations
and potentially treatment failure. SJW also induces CYP3A4, an enzyme responsible for
the elimination of indinavir, a protease inhibitor (29–31). This decreases the oral absorp-
tion and increases the metabolic elimination of indinavir potentially leading to treatment
failure for human immunodeficiency virus (HIV). On the contrary, some supplements
may interact with an object drug by potentiating their pharmacological effects on specific
receptors (32). Therefore, dietary supplements can play a very important role in the study
of drug interactions complicating a patient’s medication regimen and may have a pro-
found effect on the patient’s treatment outcome (see Chapter 3).
Chapter 11 / Dietary Supplements and Medication                                         221

               Table 2
               Ten Most Commonly Used Non-Nutrient Dietary Supplements
               1. Ginseng                    6. Echinacea
               2. Ginkgo                     7. Lecithin
               3. Garlic                     8. Chondroitin
               4. Glucosamine                9. Creatine
               5. St. John’s wort           10. Saw palmetto
                  From ref. 18.

3.1. Ginseng
   The 10 most commonly used dietary supplements are listed in Table 2 (18). Ginseng
is one of the most popular herbal supplements in the United States. There are a number
of different species of ginseng. However, the most studied forms of ginseng include just
three species: Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng),
and Panax japonicus (Japanese ginseng) (33). These species can be found in many dosage
forms including alcoholic extracts, fresh root, teas, capsules, and in combination prod-
ucts with other mineral, vitamin, and herbal ingredients (34). Ginseng has been used
therapeutically for thousands of years in Asia for a variety of illnesses and ailments. Some
of these uses vary from more traditional ones such as to increase general well-being to
more present-day uses such as to improve vitality, immune function, cognitive function,
cardiovascular function, physical performance, sexual performance, and even the treat-
ment of cancer (35). Compounds known as the ginsenosides are thought to be responsible
for the therapeutic activity of ginseng. However, because of the complexity of actions of
these compounds as well as the activity of non-ginsenoside compounds contained within
the herb, the overall activity of the herb is very complex (33). The potential interactions
with prescription medications are even less well understood and explained mainly by
case reports.
   Currently, there is one published case report of an interaction between ginseng and the
oral anticoagulant agent warfarin (36). In this case, a 74-yr-old man with a mechanical
heart valve was being anticoagulated with warfarin with International Normalized Ratios
(INRs) within the therapeutic range for more than 5 yr before deciding to begin taking
ginseng capsules. All of his other medications and diet remained the same. Two weeks
after taking the ginseng capsules, the patient’s INR dropped to a subtherapeutic level. On
discontinuation of the ginseng product, the patient’s INR returned to the therapeutic level
and continues to remain within the therapeutic range. Doses of warfarin were not adjusted.
A study in rats examining the interaction with warfarin and ginseng found conflicting
results (37). This study found no impact of ginseng on warfarin pharmacokinetics and
dynamics when the two were concomitantly administered. Although the data are sparse
and conflicting, more vigilant monitoring or the avoidance of ginseng in patients treated
with warfarin may be warranted.
   Similar to the cases of warfarin and ginseng, the human experience with an interaction
between ginseng and phenelzine is only documented in case report form. Phenelzine is
a monoamine oxidase inhibitor with many known food and drug interactions. It is used
222                                                     Part III / Influence of Food or Nutrients

for the treatment of depression. In the cases reported, upon addition of ginseng products
to therapy with phenelzine, patients developed tremulousness, headache, and sleepless-
ness (38,39). The symptoms improved with discontinuation of the ginseng. While still
being treated with phenelzine, one of these patients was inadvertently rechallenged with
ginseng many years later and experienced similar results (40).
   A case report by Becker suggested that a ginseng product containing germanium may
decrease the diuretic effect of furosemide. However, it is important to point out that
exposure to germanium, a heavy metal, may itself lead to renal failure. It is, therefore,
unclear, based on this case report, whether a true drug–herb interaction was present (41).
   An increase of plasma nifedipine concentrations was observed following the use of
ginseng, although the clinical significance of pharmacodynamic responses (e.g., blood
pressure, heart rate) was not documented. Furthermore, this investigation involved the
use of three different dietary supplements (i.e., SJW, ginseng, and ginkgo). The subjects
received all three supplements in a sequential order with a 14-d washout period between
each phase. Because the mechanisms of interactions were not known, it is unclear whether
the 14-d washout period was sufficient. Therefore, the study results could have been
confounded by the presence of multiple drug interaction (42).

3.2. St. John’s Wort
   Of all the herbal products currently marketed in the United States, SJW is probably the
most formally studied and reported in terms of the potential to cause specific interactions
with prescription medications. Its scientific name is Hypericum perforatum. It is so called
SJW because its flowers bloom by the end of June, which is the time of the feast of St.
John the Baptist. This herb has been used for thousands of years topically for many
ailments, including minor burns and wounds and in more recent times as an oral extract
to treat mild depression. SJW is a perennial plant that can be found throughout Europe,
Asia, North Africa, and in North America (43). The product tends to be standardized in
terms of its hypericin content, but as with other herbal products, there have been pub-
lished reports of discrepancies between labeled content and actual content assayed (44).
In addition to hypericin, a number of its derivatives and metabolites, such as hyperforin,
chlorogenic acid, and quercetin, may also contribute to its clinical effect.
   The dramatic ability of SJW to alter the concentrations of concomitantly administered
medications is thought to occur through two major mechanisms. First, SJW has the ability to
induce intestinal transporter (e.g., P-gp) activity. Second, the herb can increase the activity of
CYP3A4 and CYP2B6 through pregnane X receptor activation (24–26,30,31,45,46).
CYP3A4 is an enzyme responsible for the metabolism of a majority of prescription agents
and its induction has important clinical implications. Although CYP2B6 activity is also
increased by hyperforin, there are very few medications identified to be CYP2B6 sub-
strates. Therefore, the clinical relevance of CYP2B6 induction remains to be determined.
In the human small intestine, CYP3A4 and P-gp function as a coupled system to reduce
xenobiotic exposures by the host. This coupling system has the most significant influence
on the absorption of substances that are substrates of both CYP3A4 and P-gp. Drug
molecules that “escape” the initial extraction by the intestinal CYP3A4 enzymes and are
absorbed into the epithelial cells can be excreted back into the gut lumen by P-gp, poten-
tially re-exposing them to gut-wall metabolism multiple times. Induction of both P-gp
and CYP3A4 by SJW may lead to a dramatic reduction in oral bioavailability of drugs
Chapter 11 / Dietary Supplements and Medication                                          223

and can have grave implications for narrow therapeutic index agents. Decreased oral
absorption may lead to subtherapeutic serum concentrations of medicinal agents result-
ing in treatment failure.
   Even the induction of CYP3A4 alone may have grave complications for narrow thera-
peutic index agents. SJW may cause up to a sixfold induction of CYP3A4 activity.
CYP3A4 is the most important phase I oxidative enzyme in humans accounting for the
metabolism of more than 50% of prescription drugs currently used. CYP3A4 is ubiqui-
tous with the most significant concentrations found in a variety of tissues including the
liver and intestinal epithelium (47). However, in terms of drug metabolism, the most
significant locale for CYP3A4 is the liver and intestine. An induction of CYP 3A4 in the
intestinal epithelium can increase the presystemic metabolism of medicinal agents pre-
venting their absorption. This can lead to an overall decrease in the total bioavailability
of an orally administered agent. Also, an induction of CYP3A4 in the liver will increase
the systemic elimination of medicinal agents primarily metabolized by this enzyme
system. This could lead to a decrease in the systemic exposure of the agent and potentially
lost efficacy. Like P-gp, this effect is especially true for narrow therapeutic index agents.
   In addition to pharmacokinetic studies, a number of clinical trials and case reports have
corroborated the interaction between SJW and prescription medication with a narrow
therapeutic index that are substrates for P-gp, CYP3A4, or both. These trials are summa-
rized in Table 3. Most notably, there is literature published with SJW in combination with
indinavir (31), digoxin (25), cyclosporine (48,49), tacrolimus (50), irinotecan (51),
fexofenadine (52), and simvastatin (53). It has also been reported that the serum concen-
tration of norethindrone, a progestin-derivative used in some oral contraceptive prepa-
rations, can be decreased by SJW. This reduction in norethindrone concentration was
associated with increased incidence of breakthrough bleeding. However, it is not known
whether the contraceptive efficacy is negatively affected by SJW (54). Ongoing inves-
tigations are currently underway to further assess the risks and clinical implications of
this drug–herb interaction. All these results confirm that SJW may alter therapeutic
effects and drug concentrations. The alteration in therapeutic concentrations in some
cases potentially has very deleterious and dangerous consequences for affected patients.
For example, a decrease in the therapeutic concentrations of indinavir, a protease inhibi-
tor used in the treatment of HIV disease, may lead to an increase in HIV viral load or viral
resistance indicating treatment failure. Additionally, subtherapeutic concentrations of
cyclosporine or tacrolimus, medications used by organ transplant recipients to prevent
rejection, can lead to organ rejection and significant morbidity or even mortality for these
   Because of the potential for SJW to induce P-gp and CYP 3A4, it is probably prudent
to avoid using SJW in patients treated with prescription medications that are substrates
of these two enzyme systems. Most importantly, it would be imperative to avoid narrow
therapeutic index agents transported by P-gp or metabolized by CYP3A4 in order to
avoid a dangerous interaction. Table 4 is a compilation of the agents that should be used
with extreme caution with SJW. However, keep in mind that any agent that is affected by
these two pathways has the potential to be influenced by SJW and should probably be
avoided concomitantly with SJW. Patients should be carefully counseled about the
potential risks of initiating therapy with SJW and health care professionals should be
vigilant about the potential risks associated with this herbal product.
224                                                       Part III / Influence of Food or Nutrients

Table 3
Summary of Documented Drug Interactions With St. John’s Wort
Interacting Medication               Type of Report                   Reported Results
Indinavir                      Open-label trial                  Reduced mean AUC by 57%
Digoxin                        Placebo-controlled                After 10 d of therapy with
                               parallel study                      SJW, mean AUC reduced
                                                                   by 25%
Cyclosporine                   Case report (two patients)        Acute heart transplant
                                                                   rejection, subtherapeutic
                                                                   cyclosporine concentrations
Cyclosporine                   Case report                       Kidney transplant recipient
                                                                   with subtherapeutic
                                                                   cyclosporine concentrations
Tacrolimus                     Case report                       Kidney transplant recipient
                                                                   with decreased tacrolimus
                                                                   levels. Levels returned to
                                                                   baseline upon discontinuation
                                                                   of SJW
Irinotecan                     Randomized crossover              Formation of active metabolite
                                                                   decreased by 42%. Less
                                                                   myelosuppression in SJW-
                                                                   treated patient
Fexofenadine                   Open-label trial                  Single-dose SJW increased
                                                                    Cmax by 45% and decreased
                                                                    oral clearance by 20%
Simvastatin                    Double-blind crossover            Significant decrease in the
                                                                    active metabolite simvastatin
                                                                    hydroxy acid
AUC, area under the concentration-time curve; SJW, St. John’s wort.
From refs. 25,31,48–53.

   Outside the realm of pharmacokinetic interactions, SJW may also interact with a
number of medications based on pharmacodynamic properties. The agents that are par-
ticularly at risk for causing this type of reaction are antidepressants, including selective
serotonin reuptake inhibitors (SSRIs), namely paroxetine and sertraline, and agents such
as trazodone or nefazodone. There have been a number of cases of the combination of
these agents with SJW causing symptoms consistent with that of excess serotonin or
serotonin syndrome (55,56). Serotonin syndrome is generally characterized by mental
status changes, tremor, autonomic instability, myalgias, and motor restlessness (57). This
reaction is thought to occur because of hyperforin, a component of SJW that may inhibit
the reuptake of serotonin. This, in combination with a prescription SSRI or other prescrip-
tion agent that inhibits the reuptake of serotonin, may have an additive effect and predis-
pose one to the serotonin syndrome. The potential for dangerous complications owing to
Chapter 11 / Dietary Supplements and Medication                                        225

          Table 4
          Drugs That Should Be Used With Caution With SJW
          Based on Pharmacokinetic Interactions
          CYP 3A4 Substrates                           P-gp Substrates
          Antiarrhythmics                      Antiarrhythmics
            amiodarone, quinidine                digoxin, quinidine, amiodarone
          Calcium channel blockers             Calcium channel blockers
            diltiazem, verapamil,                diltiazem, verapamil
          Immunosuppresants                    Immunosuppresants
            cyclosporine, tacrolimus             cyclosporine, tacrolimus
          Protease Inhibitors                  Protease Inhibitors
             ritonavir, indinavir,                amprenavir, indinavir,
             saquinavir, nelfinavir               nelfinavir, saquinavir

serotonin syndrome cannot be understated and deaths have occurred as a result of this
syndrome. Patients who are currently being treated with SSRIs or other antidepressants
that increase the concentrations of serotonin should be warned of this potential interac-
tion and should be advised not to use SJW with these prescription medications.
3.3. Garlic
   Along the lines of potential CYP and P-gp interactions with herbal products and
prescription medication, there is some evidence emerging that may suggest garlic (Allium
sativum) might also have an effect on these two systems (58–60). Used for centuries as
a flavoring ingredient in food, garlic is also believed to carry many other beneficial
effects. In the ancient world, garlic was used for a variety of reasons, including to treat
common ailments, headaches and body weakness, epilepsy, and even hemorrhoids to
clean the arteries (61). This is very much in line with some of the more modern therapeutic
uses of garlic, which include use as an antihypertensive, a cholesterol-lowering agent, to
improve circulation, as an antiatherosclerotic, and even as a blood thinner (62). The
active component in garlic is thought to be allicin, which is only formed when garlic is
crushed. Cooking or heating destroy the necessary enzymes for the formation of allicin.
However, there still are a number of other components found within garlic products with
potential activity.
   In vitro data indicates that garlic may have an inhibitory effect on CYP2C9, 2C19,
2D6, and 3A isoenzymes (58). In contrast, an in vivo study in nine healthy volunteers,
which examined the chronic administration of garlic (greater than 3 wk), showed that
garlic decreased the systemic exposure and maximum concentrations of saquinavir, a
protease inhibitor that is a known substrate of the CYP3A4 (59). However, the exact
mechanism of the decrease was not able to be determined from this trial. Furthermore,
garlic had a bimodal effect on the serum concentrations of subjects tested. Six subjects
226                                                   Part III / Influence of Food or Nutrients

showed a decreased saquinavir systemic exposure, measured by the area under the con-
centration-time curve (AUC) during treatment with garlic, which later returned to just
below their baseline upon discontinuation of garlic. The AUC of the three other subjects
was unchanged while on garlic, but dropped significantly after the discontinuation of
garlic. The reason for this bimodal distribution in subjects was not able to be determined.
Because the overall maximal plasma concentration (Cmax) and AUC were decreased, the
data imply that chronic ingestion of garlic may have an induction effect on CYP3A4 in
the intestinal mucosa. However, because saquinavir is also a P-gp substrate, an effect on
P-gp at this time cannot be ruled out. Another trial that evaluated the effect of a variety
of herbal products, including garlic, on substrates of various different CYP isoenzymes
in healthy volunteers found that garlic had no significant effect on the CYP3A4 isoen-
zyme but did indeed have an inhibitory effect on the CYP2E1 metabolic pathway (60).
Because no effect of CYP3A4 was seen in this study, the authors argue that there may be
varying components of different garlic preparations and garlic’s effect on the CYP enzyme
system might be product-dependent. Until garlic’s mechanism for interacting with CYP or
P-gp is further evaluated, clinicians should pay particular attention to patients using
garlic while concomitantly taking prescription agents that are CYP or P-gp substrates.

3.4. Ginkgo
   Ginkgo is a popular herb that is derived from the dried leaves of Ginkgo biloba or
maidenhair, a tree that is native to China, but can be cultivated in Europe, Asia, and North
America. Use of this herb dates back to the very beginnings of ancient Chinese medicine.
Today, the herb can be found used for a variety of purposes including cognition, memory,
cerebral vascular disease, peripheral vascular disease, and multiple sclerosis, to name a
few. The active components of Ginkgo biloba are extracted from the leaves, which
contain ginkgolides A, B, C, J, and M, and bilobalide (63).
   In terms of specific drug interactions with ginkgo, there are a number of case reports
documenting possible interactions between ginkgo and the anticoagulants warfarin and
aspirin (64,65). In the reported cases, bleeding seems to be the most common result of the
concomitant use of ginkgo with other anticoagulant agents. This reaction may in part be
exacerbated by the fact that various ginkolides are capable of inhibiting platelet-activat-
ing factor (66). There have been a number of case reports of ginkgo attributed to an
increased risk of serious bleeding events (67). It may be possible that the cumulative effects
of ginkgo’s inhibition of platelet-activating factor with other anticoagulants are responsible
for the reaction. Because of the possible potential for ginkgo to increase the risk of
bleeding, clinicians should recommend patients avoid the use of this herb with any
anticoagulant therapy or prior to any scheduled surgery.
   Metabolically, there are conflicting results regarding the potential for ginkgo to affect
CYP. A published abstract reported that ginkgo had an inhibitory effect on CYP3A4 in
healthy volunteers reporting a 53% decrease in mean nifedipine (a CYP3A4 substrate)
concentration at peak time 0.5 h after 18 d of ginkgo therapy compared to nifedipine alone
(68). However, a published trial examining ginkgo’s effects on a number of different
CYP substrates found the herb had no significant effect on any of the CYP isoenzymes
tested including CYP3A4, 2D6, 1A2, and 2E1 (60). The authors of this paper argue that
different formulations of ginkgo with differing concentrations of phytochemicals and
different bioavailability might be responsible for the discrepancy between studies (60).
Chapter 11 / Dietary Supplements and Medication                                          227

Once again, until the metabolic profile of ginkgo is better understood it would be reason-
able to recommend not using the agent concomitantly with other prescription agents that
are substrates for CYP or P-gp.

3.5. Echinacea
   Echinacea is one of the most popular herbal remedies used to treat or prevent the
common cold and respiratory or urinary tract infections. During the winter months, when
cold and flu tend to be more prevalent, the demand for echinacea in retail pharmacies and
other supplement retailers across the country seems to increase. Also, echinacea can be
found incorporated into a number of throat lozenges or cough drops intended to miti-
gate the symptoms of a cold. Products are generally composed of one or a combination
of three echinacea species, E. purpurea, E. angustifolia, and E. pallida (69). Specific
drug interactions associated with the use of echinacea have not been reported. However,
there is in vitro data suggesting that echinacea may have an inhibitory effect on the
CYP3A4 enzyme (70). Although this data is in vitro and no in vivo data have yet con-
firmed the findings, those patients taking CYP3A4 metabolic substrates for medicinal
purposes would be advised to avoid the use of echinacea. Further study in vivo is certainly
warranted to further delineate the magnitude of this potential interaction.
   Additional interactions between dietary supplements and medications have been pro-
posed or are being actively investigated. These include not only herbal products but
nutrient supplements as well (Table 5).

3.6. Vitamin Supplements and Drug Interactions
   Although it is well known that a number of drugs have the potential to cause hypovi-
taminosis, it is less appreciated that vitamin supplementation may affect drug disposition.
Other nutrients may also interact with drugs—altering absorption, metabolism, and phar-
macodynamic effects. Unfortunately, most of the data are obtained from case reports
including single patients, animal models, or from in vitro investigations (Table 6). The
two better documented vitamins include folic acid and vitamin E ( -tocopherol).
   It has been established that patients receiving chronic therapy with phenytoin carry a
50% risk of folate deficiency. Ironically, supplementation of 1 mg/d folic acid may lead
to a significant decrease in serum phenytoin concentrations in 15–50% of the patients.
This interaction between folic acid and phenytoin may involve the bilateral interdepen-
dent transport and possible metabolic processes (71). Although the exact mechanism is
unknown, pharmacokinetic analysis of phenytoin suggests that folic acid may increase
the affinity of the metabolic enzyme(s) involved in the elimination of the phenytoin
without causing overall enzymatic induction (72). Although it is important to monitor for
any signs of folic acid deficiency (such as megaloblastic anemia) in patients receiving
long-term phenytoin therapy, it is as important to closely follow their serum phenytoin
concentration should folate supplementation be deemed necessary in order to avoid
breakthrough seizures secondary to subtherapeutic serum phenytoin concentrations.
   The mechanism of interactions with drugs caused by vitamin E is of particular interest.
The enhanced oral absorption of cyclosporine by water-soluble vitamin E was first
reported in pediatric patients after liver transplantation (73,74). Subsequently, a more
formal observation trial took place in liver transplant recipients. In 26 patients who failed
to achieve therapeutic blood cyclosporine concentrations despite prolonged intravenous
228                                                    Part III / Influence of Food or Nutrients

Table 5
Some Additional Proposed Interactions Between Dietary Supplements and Drugs
Supplement Ingredient            Medication
(Precipitant)                     (Object)                        Comment
S-Adenosyl-methionine         Serotonergic agents         Risk for serotonin syndrome
Calcium                       Thyroid hormone             May interfere with drug absorption
Coenzyme Q                    Warfarin                    May antagonize drug effect
Dong quai                     Warfarin                    May potentiate drug effect
Echinacea                     Immunosuppressants          Potential for altered drug
Fennel                        Fluoroquinolones            Reduced drug bioavailability
Feverfew                      NSAIDS                      Additive inhibition of prostaglandin
Folic acid                    Phenytoin                   Reduced circulating drug
Ginseng                       Oral hypoglycemics          Additive hypoglycemic effects
5-Hydroxytryptophan           Carbidopa                   May cause scleroderma-like
Iron                          ACE-inhibitors              May interfere with drug absorption
Iron                          Levodopa/Carbidopa          May interfere with drug absorption
Kava                          Benzodiazepines             Potential for additive CNS
Minerals (divalent)           Fluoroquinolones            Reduced drug bioavailability
Valerian                      Barbiturates                May potentiate sedative effects
Vitamin E                     Aspirin                     Additive antithrombotic effect
   NSAIDs, nonsteroidal anti-inflammatory drugs; ACE, angiotensin-converting enzyme; CNS, central
nervous system.
   From ref. 79.

administration or provision of daily oral cyclosporine doses higher than the normally
recommended range (>10 mg/kg/d for adults, and >30 mg/kg/d for children), concurrent
administration of 6.25 IU/kg of vitamin E liquid (D- -tocopheryl-polyethylene-glycol-
1000 succinate [TPGS]) before each oral dose of cyclosporine led to a significant improve-
ment in cyclosporine absorption. TPGS coadministration resulted in a reduction of daily
cyclosporine dose by 28.3% in 19 adult patients and 31.7% in 7 pediatric patients. Steady-
state, whole-blood cyclosporine trough concentrations were all significantly increased.
Patients who previously required intravenous administration of cyclosporine were all
successfully converted to oral therapy (75).
   Although it was initially thought that TPGS acted as a vehicle to allow lipophilic drugs,
such as cyclosporine, to be more readily absorbed, subsequent investigation showed that
TPGS is a P-gp inhibitor (76,77). This mechanism implies that coadministration of
vitamin E liquid may increase the absorption of a significant number of drugs. However,
what has not yet been determined is whether vitamin E capsule ( -tocopheryl acetate)
may cause a similar magnitude of drug interactions. It is reasonable to conclude, how-
ever, that vitamin supplementation may not appear to be completely without risks.
Chapter 11 / Dietary Supplements and Medication                                         229

Table 6
Dietary Factors That Modulate CYP Activity
       Parameters                Species            Tissue           CYP Activity
Protein supplementation         Human           Whole body          CYP1A2
Protein deficiency              Human           Whole body          CYP1A2
MCT oil supplementation         Rat             Liver               CYP1A2
Corn oil supplementation        Rat             Liver               CYP2B1, CYP2E1
Vitamin A supplementation       Rat             Skin                CYP1A1, CYP1A2
                                                Liver               CYP2A1, CYP3A2
                                                                    CYP2C6, CYP2C11
Vitamin A deficiency            Rat             Liver               CYP2C11
Thiamin deficiency              Rat             Liver               CYP2E1
Vitamin C deficiency            Guinea pig      Liver               CYP1A2
                                ODS-rat         Liver               CYP1A2 CYP3A
Vitamin E supplementation       Rat             Liver               CYP2C11
Iron deficiency                 Rat             Intestine           total CYP
Starvation                      Rat             Liver               CYP1A2, CYP2C11
                                                                    CYP2B, CYP2E1,
Caloric restriction             Rat             Liver               CYP3A
  Note: CYP3A1 and CYP3A2 are expressed in rodents but not humans. Humans express CYP3A4 and
CYP3A5. Substrate’s binding affinity to CYP3A4/5 is different from that of CYP3A1/2.
  From ref. 78.

   The area of dietary supplements is a growing topic of interest within the public and the
medical community. Unfortunately, physicians, nurses, pharmacists, and other health
care professionals, for the most part, were never formally trained in the use, efficacy, and
monitoring of these agents. However, the public trusts that health care professionals are
valuable sources of information on this subject. Indeed, this is true. There are a number
of ways health care professionals can prepare themselves to treat patients who are using
non-nutrient-containing dietary supplements and to help tailor therapy to avoid potential
interactions. First, all patients should be screened routinely for dietary supplement use.
This will not only enable clinicians to gather additional information about a patient’s
medication regimen, but will also heighten the public’s awareness of the importance of
reporting use of these products to health care professionals. Second, wherever herbals or
supplements are mentioned on the medication history, clinicians should seek out infor-
mation about that product from a reliable source. Third, practitioners should be aware of
prescription agents with many known drug interactions and they should be wary when
these agents are mentioned along with herbal products or supplements in the patient’s
medication history. If a known medicinal agent has many interactions it may be prudent
to avoid its use with other agents whose interaction profiles are not currently well under-
stood. And finally, health care professionals should explain to patients the concerns
associated with the use of non-nutrient-containing dietary supplements. Data on these
230                                                          Part III / Influence of Food or Nutrients

products in the medical literature are just currently beginning to accumulate. However,
for the most part, there still is a great deal of information, particularly in the field of non-
nutrient-containing dietary supplements and drug interactions, which is currently not
well understood. Explaining to patients the potential for dangerous interactions may
prompt them to check with a healthcare professional before considering self-treatment
with an herbal or other dietary supplement.

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Chapter 12 / Dietary Supplements and Nutrients                                           235

   12            Dietary Supplement Interaction
                 With Nutrients

                 Mariana Markell

   The retail sales (in food stores, drug stores, mass market outlets) for herbal supple-
ments in 2002 totaled more than $300 million out of pocket in the United States (1). Sales
are much greater in other markets (natural food stores, convenience stores, mail order,
internet, etc.), although more difficult to estimate. This figure does not take into account
expenditures for nutrient and other nonherbal dietary supplements, including minerals and
“antioxidant” preparations, which account for many millions of dollars more. It is estimated
that 30% of the population has used or is presently using herbal supplements (2). No
regulatory agency oversees the manufacture of herbs and dietary supplements, as the
passage of the Dietary Supplement Health Education Act in 1994, excluded them from
Food and Drug Administration (FDA) surveillance (3). Thus, the true extent and preva-
lence of interaction of dietary supplements with nutrients is not truly known, and can only
be surmised from anecdotal and historical reports, as well as few animal model studies.

   Based on the observation that herbal and nonherbal supplements may have pharma-
ceutical actions, it is reasonable to assume that interactions with nutrients can occur
through one of the following pathways (Table 1): alteration of absorption either through
alteration of intestinal uptake/transport or alteration of gastric emptying, alteration of
metabolism, including effects on the hepatic cytochrome P450 (CYP) or other enzyme
systems (e.g., -hydroxy- -methylglutaryl [HMG]-CoA reductase) or interaction with
peripheral uptake mechanisms (e.g., glucose transporter), and alteration of intestinal or
renal elimination.
   Perhaps the most worrisome of dietary supplement interactions with nutrients is that
posed by herbals or other supplements that alter renal function, including those with
diuretic action, of which there are many (Table 2). These supplements are especially
problematic in patients with kidney or heart disease, for whom they are most commonly
prescribed. They may potentiate hypokalemia, with the worst effects occurring in patients
who are taking concomitant pharmacologic diuretic therapy (4,5). Far fewer are the supple-

                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
236                                                   Part III / Influence of Food or Nutrients

         Table 1
         Mechanisms by Which Dietary Supplements Could Interfere With Nutrients
         Interference with absorption
            Alteration of gastric emptying
            Alteration of intestinal transport
         Alteration of metabolism
            Interaction with cytochrome P450 enzymes
            Interaction with molecular targets (e.g., glucose transporter)
         Interaction with metabolic enzymes (e.g., HMG-CoA reductase)
         Interference with excretion
            Alteration of renal excretion
            Alteration of gastrointestinal transit time

         Table 2
         Common Herbs With Diuretic Actions
         Buchu leaves (Barosma betulina)
         Cleavers plant (Galium aparine)
         Corn Silk (Zea mays)
         Coffee bean (Caffea arabica)
         Gravelroot root (Eupatorium purpureum)
         Horsetail plant (Equisetum spp)
         Juniper berries (Juniperus spp)
         Parsley fruit (Petroselinum sativum)
         Scotch broom (Oxydendron arboreum)
         Tea leaves (Camellia sinensis)
            From refs. 4,5.

ments (predominantly derived from fruits) that may potentiate hyperkalemia in patients
with kidney failure or aldosterone resistance, either intrinsic, as occurs with longstanding
diabetic patients who develop hyporeninemic hypoaldosteronism, or in patients who are
taking pharmacologic aldosterone antagonists (spironolactone) or angiotensin convert-
ing enzyme (ACE) inhibitors, or receptor blockers (ARBs).
   Alteration of hepatic function has been reported with herbal products that utilize the
CYP system for metabolism, especially the CYP3A fraction (6,7). Although no specific
alteration in nutrient levels has been reported, severe drug interactions can occur after
ingestion, as increased synthesis of hepatic enzymes results in decreased levels of drugs
including indinavir and cyclosporine (8,9). There are also herbal supplements available
(Table 3) that alter the action of hepatic synthetic enzymes, resulting in decreased serum
cholesterol (10).
   Interference with the absorption of nutrients can occur through ingestion of supple-
ments that either increase gut motility (decreased transit time) or create a barrier to
absorption. Laxative herbs are many (Table 4). Classically, the irritant anthroquinones,
or the other laxative herbs, that decrease transit time through the gut, could alter nutrient
absorption or increase excretion. Hypokalemia has been reported following their ingestion
(4,5). Other supplements, including grapefruit juice, have reported activities on P-glyco-
Chapter 12 / Dietary Supplements and Nutrients                                          237

           Table 3
           Common Herbal Products With Effects on Cholesterol/Lipid Metabolism
           Gugulipid (Commiphora mukul extracts)
           Garlic (Allium sativum)
           “Red rice” statin (Monascus purpureus)

           Table 4
           Common Herbs With Laxative Effects
           Aloe resin (Aloes spp)
           Buckthorn fruit (Rhamnus frangula)
           Cascara sagrada bark (Rhamnus purshiana)
           Castor bean oil (Rincus communis)
           Rhubarb root (Rheum palmatum)
           Senna leaves and pods (Cassia spp)
           Yellow dock root (Rumex crispus)
              From refs. 4,5.

protein and affect drug absorption. Theoretically, these substances could affect nutrient
absorption as well (11).
   Herbs that are high in mucilage (water-soluble, hydrocolloidal fiber; Table 5), includ-
ing the demulcents, can theoretically create a barrier to absorption of nutrients across the
gut wall—with the greatest effect on absorption of glucose (12). These herbs may also
slow gastric emptying, resulting in altered nutrient absorption.
   Finally, there are herbs and dietary supplements with miscellaneous actions. Hypogly-
cemia may be potentiated by supplements that alter insulin secretion, sensitivity of the
insulin receptor to insulin, or that have insulin-like activity (see Table 6).
   Probably most worrisome, is that as herbals and other supplements remain poorly
regulated in the United States, untoward effects are often not reported, and effects on
nutrient disposition and elimination are for the most part, unknown, especially in the
patient who ingests multi-ingredient formulations.

3.1. Effects on Potassium
   Herbs are commonly prescribed for the purpose of diuresis, both in patients with
kidney as well as heart disease (13). As is true of the pharmacologic diuretics, potential
for hypokalemia and hypomagnesemia exists, especially if abused. The mechanism by
which diuretic action occurs has not been elucidated for most supplements. Interestingly,
dandelion (Taraxacum officianale) root contains an inulin-like substance that may obli-
gate an osmotic diuresis, while its leaves are high in potassium and could offset potassium
wasting (5). Hypokalemia can also be potentiated by licorice (Glycerrhiza glabra root)
(14), whose saponin component has aldosterone-like activity, resulting in renal potas-
sium wasting through actions on the distal tubule, as well as sodium and fluid retention,
and hypertension in susceptible people (15).
238                                                   Part III / Influence of Food or Nutrients

          Table 5
          Common Herbs With Hydrocolloidal Activity
          Aloe gel (Aloe vera)
          Carageenan gum (Gigartina mamillosa)
          Fenugreek seed (Trigonella foenum-graecum)
          Flax seed or meal (Linum usitatissimum)
          Guar gum seed endosperm (Cyamopsis spp)
          Konjac powder—glucommanan from tubers (Amorphophallus konjac)
             From refs. 4,5.

          Table 6
          Common Herbs With Effects on Blood Glucose
          Bitter melon fruit (Momordica charantia)
          Fenugreek seeds (Trigonella foenum-graecum)
          Garlic clove (Allium sativum)
          Ginseng root (Panax ginseng)
          Gymnema leaves (Gymnema sylvestre)
             From refs. 4,5.

   Hypokalemia may also be exacerbated by herbs with laxative effects (Table 4), includ-
ing Cascara sagrada (Rhamnus purshiana) bark or Senna (Cassia spp) leaves and pods,
Aloe vera resin, and Yellow Dock root (Rumex crispus). The effect is presumably through
decreased transit time through the bowel, although exact mechanisms are unknown.
   In patients with hyporeninemic hypoaldosteronism (Type IV renal tubular acidosis),
or those taking aldosterone-blocking drugs such as spironolactone or ACE inhibitors or
ARBs—herbs or supplements that are high in potassium may potentiate hyperkalemia. Any
product derived from fruit substances will have a high potassium load, including “Tibetan
Noni” (Indian Mulberry, Morinda citrifolia), Dandelion leaf (see earlier), and Star Fruit
(Carambola spp). The latter is especially worrisome in patients with renal failure as it has
been associated with seizures and coma (16). Additionally, the pickling process alters
oxalate metabolism and has been reported to cause oxalate kidney stones (17).

3.2. Effects on Gastrointestinal Absorption
   Herbs that are high in mucilage (Table 3) contain hydrocolloidal fibers that increase
viscosity of gut contents and theoretically delay gastric emptying (12) and may act as a
barrier to absorption, especially of glucose (18). These substances are classically used for
“stabilization of blood glucose” or as demulcents to sooth irritated gastrointestinal mucosa.

3.3. Effects on Blood Glucose
   In addition to the mucilaginous herbs just mentioned, there are substances that may
affect blood glucose through different mechanisms (Table 6), including direct effects on
peripheral glucose utilization via alteration of glucose transport (19) or insulin sensitivity
(20) purported to underlie the hypoglycemic effects of the Philippine herb Banaba,
Chapter 12 / Dietary Supplements and Nutrients                                                          239

Langerstoemia speciosum L. There is evidence that Asian ginseng (Panax ginseng) may
alter glucose utilization through enhancement of aerobic glycolysis through -agonist
activity and increased enzyme activity of the tricarboxylic acid cycle (21), and Bitter
melon (Momordica charantia) has components that are structurally similar to animal
insulins (22).
    Gymnema sylvestre has the odd property of suppressing sweet taste, and thus avoid-
ance of simple sugars may underlie its actions (23), although there are data suggesting
it causes release of insulin from pancreatic -cells and may alter glucose tolerance by that
mechanism (24).

3.4. Effects on Lipid Metabolism
   Several herbs or herbal products have documented effects on lipid metabolism. Garlic
(Allium sativum) may affect cholesterol through inhibition of synthesis by sulfur-con-
taining compounds (25), and triglyceride metabolism through inhibition of fatty acid
synthesis (26).
   Cholestin, a dietary supplement that is prepared by fermentation of rice with red yeast
(Monascus purpureus), has clear inhibitory actions on HMG-CoA reductase, containing
a compound monacolin K that is identical in structure to mevinolin (lovastatin) (27). The
product has similar toxicities to lovastatin, including a report of rhabdomyolysis occur-
ring in a transplant recipient receiving cyclosporine (28). Cholestin has been removed
from the US market by the FDA (29), but is available in other countries.
   Guggulipid, an Ayruvedic preparation of extracts from the Commiphora mukul tree,
contains stereoisomers E- and Z-guggulsterone that act as agonists for the bile acid
receptor FXR, a regulator of cholesterol homeostasis. This mechanism may underlie the
purported lipid-lowering effects of the supplement (30).

   Dietary supplements are largely unregulated in terms of required documentation of
interactions at present, and are available without prescription to anyone who enters a
health food store or pharmacy. Although generally benign in action, some supplements
possess potent pharmacologic activity that can have profound effects on nutrient levels
in the body, including potassium and glucose homeostasis, cholesterol and triglyceride
metabolism, and undoubtedly, effects that have not yet been recognized. We need to
remain aware of altered nutrient status and the potential for dietary supplements to be
responsible. It behooves those of us who are concerned with nutrition, to stay abreast of
the developments in supplement marketing and development, in order to advise our
patients about the risks and benefits of supplement ingestion, and guide their choices in
an informed manner.

 1. Blumenthal M. Market Report. Herbalgram 2002;55:60
 2. Robin K. Market Report. Herbalgram 2002;56:53
 3. Khatcheressian LA. Regulation of dietary supplements: five years of DSHEA. Food Drug Law J
 4. Brinker F. Herb Contraindications and Drug Interactions. Eclectic Institute, Sandy OR, 1997, pp. 102–103.
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 5. Blumenthal M. (ed.). The Complete German Commission E Monographs. American Botanical Council,
    Integrative Medicine Communications, Boston, MA, 1998
 6. Liu GT. Effects of some compounds isolated from Chinese medicinal herbs on hepatic microsomal cyto-
    chrome P-450 and their potential biological consequences. Drug Metab Rev 1991;23(3–4):439–465.
 7. Zhou S, Gao Y, Jiang W, Huang M, Xu A, Paxton JW. Interactions of herbs with cytochrome P450. Drug
    Metab Rev 2003 Feb;35(1):35–98.
 8. James JS. St. John’s Wort warning: do not combine with protease inhibitors, NNRTIs. AIDS Treat News
    2000;Feb 18(No 337):3–5.
 9. Bauer S, Stormer E, Johne A, et al. Alterations in cyclosporin A pharmacokinetics and metabolism during
    treatment with St John’s wort in renal transplant patients. Br J Clin Pharmacol 2003;55(2):203–211.
10. Low Dog T, Riley D. Management of Hyperlipidemia. Altern Ther Health Med 2003;9(3):28–40.
11. Tian R, Koyabu N, Takanaga H, Matsuo H, Ohtani H, Sawada Y. Effects of grapefruit juice and orange
    juice on the intestinal efflux of P-glycoprotein substrates. Pharm Res 2002;19(6):802–809.
12. Begin F, Vachon C, Jones JD, Wood PJ, Savoie L. Effect of dietary fibers on glycemia and insulinemia
    and on gastrointestinal function in rats. Can J Physiol Pharmacol 1989;67(10):1265–1271.
13. Kinne-Saffran E, Kinne RK. Herbal diuretics revisited: from “wise women” to William Withering. Am
    J Nephrol 2002;22(2–3):112–118.
14. Walker BR, Edwards CR. Licorice-induced hypertension and syndromes of apparent mineralocorticoid
    excess. Endocrinol Metab Clin North Am 1994;23(2):359–377.
15. Armanini D, Lewicka S, Pratesi C, et al. Further studies on the mechanism of the mineralocorticoid
    action of licorice in humans. J Endocrinol Invest 1996;19(9):624–629.
16. Neto MM, Da Costa JA, Garcia-Cairasco N, Netto JC, Nakagawa B, Dantas M. Intoxication by star fruit
    (Averrhoa carambola) in 32 uraemic patients: treatment and outcome. Nephrol Dial Transplant
17. Chen CL, Fang HC, Chou KJ, Wang JS, Chung HM. Acute oxalate nephropathy after ingestion of star
    fruit. Am J Kidney Dis 2001;37(2):418–422.
18. Frati Munari AC, Benitez Pinto W, Raul Ariza Andraca C, Casarrubias M. Lowering glycemic index of
    food by acarbose and Plantago psyllium mucilage. Arch Med Res 1998;29(2):137–141.
19. Liu F, Kim J, Li Y, Liu X, Li J, Chen X. An extract of Lagerstroemia speciosa L. has insulin-like glucose
    uptake-stimulatory and adipocyte differentiation-inhibitory activities in 3T3-L1 cells. J Nutr
20. Wang HX, Ng TB. Natural products with hypoglycemic, hypotensive, hypocholesterolemic,
    antiatherosclerotic and antithrombotic activities. Life Sci 1999;65(25):2663–2677.
21. Wang BX, Zhou QL, Yang M, Cui ZY, Liu YQ. Ikejima T. Hypoglycemic mechanism of ginseng
    glycopeptide. Acta Pharmacol Sin 2003;24(1):61–66
22. Basch E, Gabardi S, Ulbricht C. Bitter melon (Momordica charantia): a review of efficacy and safety.
    Am J Health Syst Pharm 2003;60(4):356–359.
23. Ye W, Liu X, Zhang Q, Che CT, Zhao S. Antisweet saponins from Gymnema sylvestre. J Nat Prod
24. Persaud SJ, Al-Majed H, Raman A, Jones PM. Gymnema sylvestre stimulates insulin release in vitro by
    increased membrane permeability. J Endocrinol 1999;163(2):207–212.
25. Yeh YY, Liu L. Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and
    animal studies. J Nutr 2001;131(3s):989S–93S.
26. Yeh YY, Yeh SM. Garlic reduces plasma lipids by inhibiting hepatic cholesterol and triacylglycerol
    synthesis. Lipids. 1994;29(3):189–193.
27. Man RY, Lynn EG, Cheung F, Tsang PS, O K. Cholestin inhibits cholesterol synthesis and secretion in
    hepatic cells (HepG2). Mol Cell Biochem 2002;233(1–2):153–158.
28. Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus)
    in a renal transplant recipient. Transplantation 2002;74(8):1200–1201.
29. McCarthy M. FDA bans red yeast rice product. Lancet 1998;351:1637
30. Urizar NL, Moore DD. Gugulipid: A Natural Cholesterol-Lowering Agent. Annu Rev Nutr
Chapter 13 / Drug-Induced Changes                 241

                    DISPOSITION, AND EFFECT
242   Part IV / Influence of Pharmaceuticals
Chapter 13 / Drug-Induced Changes                                                        243

   13            Drug-Induced Changes
                 to Nutritional Status

                 Jane M. Gervasio

   Drug-induced changes to nutritional status may be a direct or indirect consequence of
the drug or chemical. Medications may affect the patient’s nutritional status by altering
body weight, altering taste perception (thereby decreasing intake), altering macronutri-
ent metabolism, decreasing nutrient absorption, or depleting essential vitamins and min-
erals. Either by the drug’s mechanism of action or by its adverse effects, patient’s
nutritional status may be affected. Recognizing and acknowledging drug-induced changes
to nutritional status is imperative for optimal patient care.

   Treatment with medications for therapeutic purposes may result in an adverse effect
of weight gain. Psychotropic medications are the most commonly reported group of
medications associated with weight gain. This drug-induced weight gain can result in
increased risk for diabetes, coronary artery disease, and other health-related problems
(1). Negative self-image from weight gain can further complicate the patient’s success
with psychotropic therapy (2). Psychotropic medications associated with large weight
gain include chlorpromazine, clozapine, olanzapine, valproate products, lithium, ami-
triptyline, imipramine, and mirtazapine, although many of the remaining antipsychotic
and antidepressant drugs have been associated with some weight gain (3).
   Other medications, in addition to psychotropic medications, have been reported to
increase body weight. More commonly associated drugs include alcohol, -blockers,
insulin, oral contraceptives, estrogen, and methylprogesterone (4,5).
   Reported adverse effects of testosterone, testosterone derivatives, and selective estro-
gen receptor modulators include weight gain. Subsequently, these drugs have been used
to facilitate weight gain in the malnourished patient. Oxandrolone, a testosterone deriva-
tive, is Food and Drug Administration approved to promote weight gain in patients who
have lost weight as a result of chronic infection, surgery, or severe trauma (Prod Info:
Oxandrin 1997). Smoked marijuana, oral dronabinol, and anabolic steroids have been

                            From: Handbook of Drug–Nutrient Interactions
           Edited by: J. I. Boullata and V. T. Armenti © Humana Press Inc., Totowa, NJ
244                                                  Part IV / Influence of Pharmaceuticals

successfully used for the promotion of weight gain in patients with human immunodefi-
ciency virus/acquired immunodeficiency virus syndrome (HIV/AIDS) (6,7).
   Drug-associated weight gain does not regress easily, particularly given the degree of
adiposity in the weight gain. The extent of weight change depends on the specific drug,
the dosage, and the duration of treatment (3). The clinician must assess each patient’s
clinical presentation. Lower dosages or alternative medications within a therapeutic
category may need to be instituted. For example, psychotropic medications such as
fluoxetine, isocarboxazide, and topiramate are associated with weight loss and may be
an alternative to other medications. Lower dose oral contraceptives and estrogen prod-
ucts may alleviate the problem of increased weight seen with this class of drugs (8).
   The clinician must also assess true weight gain from the medication before changing
or initiating new treatment. Patients starting hormone replacement therapy associate
weight gain with their medication when in fact it may solely be a result of their entrance
into menopause (9). Patients experiencing relief from symptoms of depression may eat
more or overindulge. Patient education concerning body changes, proper diet, and exer-
cise must be incorporated into the overall care of the patient.

    Drugs associated with weight loss are predominantly central nervous system stimu-
lants. Although the stimulants’ anorexic properties have been used for weight loss in
obese patients, many times it is an unwanted adverse effect. Children receiving stimulant
medications for attention deficit disorder may also have minor growth suppression as
well as weight loss, but this does not appear to affect adult height or weight (10). More
common drug stimulants include amphetamine, caffeine, dextroamphetamine, meth-
ylphenidate, and theophylline.
    Other medications that may exhibit an anorexic adverse effect include antihistamines,
bethionol, dacarbazine, epirubicin, etoposide, fluoxetine, fluvoxamine, perhixiline,
pimozide, sibutramine, temozolomide, trazodone, and zonisamide.
    Alcohol intake in women and nicotine intake in both men and women are associated
with lower body weight. The mechanism of action of alcohol or nicotine weight loss is
unknown. Perkins and colleagues (11) showed a significant thermogenic effect with
nicotine alone or in combination with alcohol in men but not women. Alcohol alone in
either men or women and nicotine alone in women showed no thermogenic effect. Hence,
it is speculated that in women, nicotine acts by suppressing appetite but more research
is needed.
    The clinician must ascertain whether patient weight loss is related to a medication or
is indicative of another underlying condition. The advantages relative to the disadvan-
tages in discontinuing a medication must be weighed against the patient’s unwanted
weight loss. Lower dosages or alternative medications may be necessary. Drug holidays
in children receiving stimulants may be indicated (12).
  Medication-induced changes to an individual’s perception of taste can result in
decreased oral intake and weight loss (13,14). Taste is mediated by chemosensory
nerves that respond to stimulatory chemicals by direct receptor binding, opening ion
channels, or second messenger systems using cyclic nucleotides and phosphorylated
Chapter 13 / Drug-Induced Changes                                                         245

inositol (15,16). Medications disrupting these cellular processes may result in symptoms
of ageusia (loss of taste), dysgeusia (distortion of taste), hypogeusia (decreased sense of
taste), and phantogeusia (gustatory hallucination) (Table 1) (15–18).
   Dry mouth (xerostomia) is also associated with altering taste perception. Xerostomia
results from the suppression of saliva production. Decreased saliva production alters the
ion concentrations between the saliva and the plasma resulting in decreased taste sensa-
tion. Many drugs are associated with xerostomia, especially medications with anticho-
linergic properties. Medications often associated with xerostomia include amitriptyline,
brompheniramine, bumetanide, cetirizine, cyclopentolate, cyproheptadine, didanosine,
diphenhydramine, flecainide, flunitrazepam, granisetron, imipramine, isoniazid, lorat-
adine, mesalamine, molindone, nizatidine, nomifensine, nortriptyline, ondansetron,
olanzapine, orphenadrine, oxybutinin, pentoxyfylline, procainamide, propantheline,
rimantadine, selegiline, sertraline, terfenadine, trazodone, and trimethobenzamide (15).
   If the offending medications cannot be discontinued, or the dosage decreased, supple-
mental therapy may be offered. Masking techniques include chewing sugarless gum or
use of lozenges or breath mints to help alleviate dry mouth or altered taste. Artificial
saliva spray and pilocarpine oral tablets have been used successfully for xerostomia.
Davies and colleagues (19) reported statistically significant improvement in xerostomia
symptoms with 5mg of pilocarpine three times a day over artificial saliva spray. Although
both therapies improved dry mouth symptoms, many patients preferred the convenience
of the saliva spray (19).
   Toothpaste containing betaine has been reported to reduce xerostomia in patients with
chronic dry mouth. In a double-blind, crossover study, 60% of patients reported improve-
ment from their symptoms of dry mouth after using toothpaste containing betaine. No
changes were reported in saliva flow rates, oral mucosa, or mouth microflora (20).
   Conflicting reports have been shown using zinc supplementation for the treatment of
taste disturbances (18,21). Impaired taste sensation is a clinical manifestation of zinc
deficiency. A variety of etiological factors have been attributed to zinc deficiency includ-
ing drug therapy. If the patient is experiencing taste disturbances from zinc deficiency,
administration of zinc sulfate may be beneficial.
   The implementation of zinc therapy is not indicated for everyone. Souder et al. (22)
reported 34% of patients with chemosensory disorders were treated with zinc, but only
6% of those patients experienced any relief of symptoms. Careful assessment of the
underlying cause of the taste disturbance must be performed.

   One of the primary functions of the gastrointestinal (GI) tract is to provide the body
with a continual supply of water, electrolytes, and nutrients. The GI tract is composed of
the following layers: the serosa, a longitudinal muscle layer, a circular muscle layer, the
submucosa, and the mucosa. The innervation of the GI tract is supported by the intrinsic
nervous system. The intrinsic nervous system controls most of the GI functions under the
direction of the autonomic nervous system. Sympathetic and parasympathetic nervous
signals from the brain to the GI tract strongly effect the degree of activity of the intrinsic
nervous system. Acetylcholine and norepinephrine are the primary neurotransmitters for
the parasympathetic and sympathetic system, respectively. Additional GI neurotransmit-
ter receptors include cholinergic, histaminic, dopaminergic, opiate, serotonergic, and
246                                              Part IV / Influence of Pharmaceuticals

Table 1
Drug-Induced Taste Disorders
      Drug                 Taste Defect            Drug                Taste Defect
Acemetacin               D                    Bretylium              H-salt
Acetazolamide            D-acid               Bromocriptine          P
Acetylsulfosalicyclic    D                    Bupropion              D
Adriamycin               D                    Butorphanol            D
Albuterol                D                    Cadmium                D-metallic
Alcohol                                       Calcifediol            D-metallic
Allopurinol              D-metallic           Calcitriol             D-metallic
Alprazolam               H                    Calcitonin             D-metallic, P-salt
Ambifylline              D-bitter             Calcium Salts          D-metallic
Amethocaine              D-bitter/sweet       Captopril              A,D-bitter, P-
Amezinium                D                    Carbamazepine          A, H, P
Amiloride                A, D-salt, H         Carbenicillin          D
Amiodarone               D                    Carbimazole            H
Amiloride                A, D-salt            Carboplatin            H
Amitriptyline            H                    Carmustine             D-metallic
Amlodipine               D                    Cefacetrile            D, H
Amonafide                D                    Cefadroxil             D
Amphotericin B           H, P-metallic        Cefamandole            D
Amphetamine              D- bitter/sweet      Cefpirome              D
Ampicillin               H                    Cefodizime             D
Amrinone                 H